Combination therapy with Axl inhibitor and immune checkpoint modulator or oncolytic virus

ABSTRACT

An Axl inhibitor and one or more immune checkpoint (activity) modulators and/or one or more oncolytic viruses, for use in the prevention, treatment or management of cancer, wherein the Axl inhibitor and the one or more immune checkpoint (activity) modulators and/or the one or more oncolytic viruses are administered concurrently, separately or sequentially; compositions containing such components in combination; and methods of treating cancer in a patient by administering such components in combination.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 15/577,804 filedNov. 29, 2017, which is the U.S. national phase of PCT Application No.PCT/GB2016/051542 filed on May 27, 2016, which claims priority to GBPatent Application No. 1509338.8 filed on May 29, 2015 and GB PatentApplication No, 1516442.9 filed on Sep. 16, 2015, the disclosures ofwhich are incorporated in their entirety by reference herein.

The present invention relates to a combination therapy. In particular,although not exclusively, it concerns combination therapies comprisingan Axl inhibitor and one or more immune checkpoint (activity) modulatorsand/or one or more oncolytic viruses for the prevention, treatment, ormanagement of cancer.

All of the protein kinases that have been identified to date in thehuman genome share a highly conserved catalytic domain of around 300 aa.This domain folds into a bi-lobed structure in which resides ATP-bindingand catalytic sites. The complexity of protein kinase regulation allowsmany potential mechanisms of inhibition including competition withactivating ligands, modulation of positive and negative regulators,interference with protein dimerization, and allosteric or competitiveinhibition at the substrate or ATP binding sites.

Axl (also known as UFO, ARK, and Tyro7; nucleotide accession numbersNM_021913 and NM_001699; protein accession numbers NP_068713 andNP_001690) is a receptor protein tyrosine kinase (RTK) that comprises aC-terminal extracellular ligand-binding domain and N-terminalcytoplasmic region containing the catalytic domain. The extracellulardomain of Axl has a unique structure that juxtaposes immunoglobulin andfibronectin Type III repeats and is reminiscent of the structure ofneural cell adhesion molecules. Axl and its two close relatives, Mer/Nykand Sky (Tyro3/Rse/Dtk), collectively known as the Tyro3 family ofRTK's, all bind and are stimulated to varying degrees by the sameligand, Gas6 (growth arrest specific-6), a ˜76 kDa secreted protein withsignificant homology to the coagulation cascade regulator, Protein S. Inaddition to binding to ligands, the Axl extracellular domain has beenshown to undergo homophilic interactions that mediate cell aggregation,suggesting that one important function of Axl may be to mediatecell-cell adhesion.

Axl is predominantly expressed in the vasculature in both endothelialcells (EC's) and vascular smooth muscle cells (VSMC's) and in cells ofthe myeloid lineage and is also detected in breast epithelial cells,chondrocytes, Sertoli cells and neurons. Several functions includingprotection from apoptosis induced by serum starvation, TNF-α or theviral protein E1A, as well as migration and cell differentiation havebeen ascribed to Axl signaling in cell culture. However, Axl−/− miceexhibit no overt developmental phenotype and the physiological functionof Axl in vivo is not clearly established in the literature.

The overexpression of Axl and/or its ligand has also been reported in awide variety of solid tumor types including, but not limited to, breast,renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, anduveal melanoma as well as in myeloid leukemia's. Furthermore, itpossesses transforming activity in NIH3T3 and 32D cells. It has beendemonstrated that loss of Axl expression in tumor cells blocks thegrowth of solid human neoplasms in an in vivo MDA-MB-231 breastcarcinoma xenograft model. Taken together, these data suggest Axlsignaling can independently regulate EC angiogenesis and tumor growthand thus represents a novel target class for tumor therapeuticdevelopment.

The expression of Axl and Gas6 proteins is upregulated in a variety ofother disease states including endometriosis, vascular injury and kidneydisease and Axl signaling is functionally implicated in the latter twoindications. Axl-Gas6 signaling amplifies platelet responses and isimplicated in thrombus formation. Axl may thus potentially represent atherapeutic target for a number of diverse pathological conditionsincluding solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, non-small cell lung carcinoma and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoporosis, osteoarthritis and cataracts.

U.S. Published Patent Application No. 20070213375, U.S. Published PatentApplication No. 20080153815, U.S. Published Patent Application No.20080188454, U.S. Published Patent Application No. 20080176847, U.S.Published Patent Application No. 20080188455, U.S. Published PatentApplication No. 20080182862, U.S. Published Patent Application No.20080188474, U.S. Published Patent Application No. 20080117789, U.S.Published Patent Application No. 20090111816, PCT Published PatentApplication No. WO 2007/0030680, PCT Published Patent Application No. WO2008/045978, PCT Published Patent Application No. WO 2008/083353, PCTPublished Patent Application No. WO 2008/0083357, PCT Published PatentApplication No. WO 2008/083367, PCT Published Patent Application No. WO2008/083354, PCT Published Patent Application No. WO 2008/083356, PCTPublished Patent Application No. WO 2008/080134, PCT Published PatentApplication No. WO 2009/054864, and PCT Published Patent Application No.WO 2010/083465 disclose compounds which are useful as Axl inhibitors.

Immune responses to cancer can lead to control and even elimination oftumors. Therapeutic targeting of tumor immune regulators has resulted inthe development of successful immunotherapeutic approaches for cancertreatment. Immune modulatory antibodies that directly enhance theactivity of tumor-specific effector T cells (T_(eff)) and eliminateimmune suppressive regulatory T cells (T_(reg)) have earned significantrecent attention. These agents, commonly called “immune checkpoint(activity) modulators”, modify the activity of regulators of T cellimmunity, for example block the activity of negative regulators of Tcell immunity, such as a cytotoxic T-lymphocyte antigen 4 (CTLA-4) andprogrammed death receptor-1 (PD-1) (Kyi et al., 2014; Lu et al., 2014;Grosso et al., 2013). The term “immune checkpoint (activity) modulators”as used herein is intended to include immune checkpoint inhibitors, Tcell co-stimulatory agonists, and dendritic cell co-stimulatory agonists(Ai and Curran, Cancer Immmmol. Immunother., 3 Jan. 2015, Epublication).

FDA approval of anti-CTLA-4 antibody Yervoy™ ipilimumab (2012) and oftwo anti-PD-1 antibodies Keytruda™ pembrolizumab (2014) and Opdivo™nivolumab (2014) demonstrated that ‘releasing the brakes’ intumor-specific T cells is very efficient in treatment of highlyimmunogenic cancer types, such as melanoma. In March 2015, FDA expandeduse of nivolumab by approving it for treatment on non-small cell lungcancer (NSCLC). The checkpoint inhibitors are currently in clinicaltrials in several cancer types including bladder cancer, kidney cancerand head-and-neck cancer (Lu et al., 2014). Despite this success,immunotherapy against poorly immunogenic cancers remains a challenge.Co-administration with a second drug to enhance or prime the effect ofimmune checkpoint (activity) modulators by inhibiting resistancemechanisms is therefore an important goal for the pharmaceuticalindustry.

Whilst various combination therapies may have been previously suggestedto target the prevention or treatment of cancer, it is not possible tohypothesise with confidence whether a given combination will actuallyelicit a beneficial response. Moreover, it is almost impossible topredict whether a synergistic effect could or would be obtained from acertain combination of therapeutic agents.

Accordingly, in a first aspect, the present invention is based on thesurprising observation that the combination of an Axl inhibitor and oneor more immune checkpoint (activity) modulators provides a significantlybetter therapeutic profile than current single agent therapies or othercombination therapies utilising Axl inhibitors. Encompassed by theinvention, therefore, are combination therapies of an Axl inhibitor withone or more immune checkpoint (activity) modulators that have asynergistic potency and/or therapeutic effect, e.g. a synergy existsbetween the Axl inhibitor and the one or more immune checkpoint(activity) modulators when co-administered. Preferably, such combinationtherapies also reduce or avoid unwanted or adverse effects. In certainembodiments, doses of existing immune checkpoint (activity) modulatorscan be reduced or administered less frequently in using the combinationtherapies of the invention, thereby increasing patient compliance,improving therapy and reducing unwanted or adverse effects.

Accordingly, in a first aspect, this invention is directed to an Axlinhibitor and one or more immune checkpoint (activity) modulators foruse in the prevention, treatment or management of cancer, wherein theAxl inhibitor and the one or more immune checkpoint (activity)modulators are administered concurrently, separately or sequentially.

In one preferred embodiment, the Axl inhibitor is an anti-Axl antibody.

In an alternative preferred embodiment, the Axl inhibitor is a compoundof formula (I):

wherein:

-   R¹, R⁴ and R⁵ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R⁸,    —C(O)N(R⁶)R⁷, and —C(═NR⁶)N(R⁶)R⁷;-   R² and R³ are each independently a polycyclic heteroaryl containing    more than 14 ring atoms optionally substituted by one or more    substituents selected from the group consisting of oxo, thioxo,    cyano, nitro, halo, haloalkyl, alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heteroaryl, optionally substituted heterocyclyl,    —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—C(O)OR⁸,    —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2),    —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,    —R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1    or 2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p    is 0, 1 or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);-   or R² is a polycyclic heteroaryl containing more than 14 ring atoms    as described above and R³ is selected from the group consisting of    aryl and heteroaryl, where the aryl and the heteroaryl are each    independently optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)², —R¹³—N(R¹²)—R¹⁴—N(R¹²)², —R¹³—N(R¹²)²,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)²,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)—¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2);-   or R³ is a polycyclic heteroaryl containing more than 14 ring atoms    as described above, and R² is selected from the group consisting of    aryl and heteroaryl, where the aryl and the heteroaryl are each    independently optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)²,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)², —R¹³—N(R¹²)—R¹⁴—N(R¹²)², —R¹³—N(R¹²)²,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)²,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)N(R¹²)₂ (where    t is 1 or 2);-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,    —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷, together with    the common nitrogen to which they are both attached, form an    optionally substituted N-heteroaryl or an optionally substituted    N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;-   each R⁹ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹⁰ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,    —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R¹²'s, together with the    common nitrogen to which they are both attached, form an optionally    substituted N-heterocyclyl or an optionally substituted    N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain and an optionally substituted straight or branched alkenylene    chain; and-   each R¹⁴ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain and an    optionally substituted straight or branched alkenylene chain;-   as an isolated stereoisomer or mixture thereof or as a tautomer or    mixture thereof, or a pharmaceutically acceptable salt or N-oxide    thereof.

In addition, in a second aspect, this invention provides methods ofpreventing, treating or managing cancer in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor, in concurrent,separate or sequentially combination with a therapeutically orprophylactically effective amount of one or more immune checkpoint(activity) modulators.

In a third aspect of the invention, there is provided an Axl inhibitor,for use in the prevention, treatment or management of cancer, whereinthe prevention, treatment or management of cancer is in a patient towhom an immune checkpoint (activity) modulator has been or will beadministered.

In a fourth aspect, the invention provides a method of preventing,treating or managing cancer in a patient to whom an immune checkpoint(activity) modulator has been or will be administered, the methodcomprising administering to a patient in need thereof a therapeuticallyor prophylactically effective amount of an Axl inhibitor.

In a fifth aspect of the invention, there is provided a pharmaceuticalcomposition comprising an Axl inhibitor, one or more immune checkpoint(activity) modulators, and a pharmaceutically acceptable excipient.

These aspects are based on the surprising observation that there is asynergistic interaction between an Axl inhibitor and one or more immunecheckpoint (activity) modulators, which provides a significantly bettertherapeutic profile than when each agent is used in isolation, i.e.there is an effect which surpasses expecations based on additiveeffects.

In a sixth aspect of the invention, there is provided an Axl inhibitorand one or more oncolytic viruses, for use in the prevention, treatmentor management of cancer, wherein the Axl inhibitor and the one or moreoncolytic viruses are administered concurrently, separately orsequentially.

This aspect is based on the surprising observation that the combinationof an Axl inhibitor and one or more oncolytic viruses provides asignificantly better therapeutic profile than current single agenttherapies or other combination therapies utilising Axl inhibitors.Encompassed by the invention, therefore, are combination therapies of anAxl inhibitor with one or more oncolytic viruses that have a synergisticpotency and/or therapeutic effect, e.g. a synergy exists between the Axlinhibitor and the one or more oncolytic viruses when co-administered.Preferably, such combination therapies also reduce or avoid unwanted oradverse effects. In certain embodiments, doses of existing oncolyticviruses can be reduced or administered less frequently in using thecombination therapies of the invention, thereby increasing patientcompliance, improving therapy and reducing unwanted or adverse effects.

In particular, it is believed that the oncolytic virus functions tostimulate an immune response in tumours, thereby potentiating the immuneresponse in combination with the Axl inhibitor. The virus generates longstranded RNA molecules that drive an innate response via toll-likereceptors (TRL) and type I interferon (IFNa) activation, which appearsto potentiate the effect of the Axl inhibitor since Axl signalling has asuppressive effect on TRL/IFNa. Although the prior art (e.g. Lichty, B.D. et al. Nature Reviews 2014, 14, 559-567; WO 2014/158811) describescombination therapies comprising oncolytic viruses and immune checkpointinhibitors, there is no indication that combination therapies comprisingoncolytic viruses and Axl inhibitors, which act at different biochemicaltargets compared to immune checkpoint inhibitors, would provide thesynergistic effects observed.

These effects are even more surprising and pronounced when the Axlinhibitor and one or more oncolytic viruses are used in furthercombination with one or more immune checkpoint (activity) modulators,wherein the Axl inhibitor, the one or more oncolytic viruses and the oneor more immune checkpoint (activity) modulators are administeredconcurrently, separately or sequentially. Particularly in relation to“cold” tumours, which have low immunogenicity and a poor response toimmune checkpoint inhibitors, Axl inhibition in combination withoncolytic virus treatment has surprisingly been found to provide apotentiated immune response, and significantly reinforce the effect ofimmune checkpoint modulation (especially checkpoint inhibition).

Preferred examples of oncolytic viruses include reovirus, Newcastledisease virus, adenovirus, herpes virus (e.g. herpes simplex 1), poliovirus, mumps virus, measles virus, influenza virus, vaccinia virus,rhabdovirus, parvovirus, vesicular stomatitis virus, and derivatives andvariants thereof.

In a seventh aspect of the invention, there is provided a method ofpreventing, treating or managing cancer in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in concurrent,separate or sequential combination with a therapeutically orprophylactically effective amount of one or more oncolytic viruses.

This method may further comprise administering to the patient in needthereof a therapeutically or prophylactically effective amount of one ormore immune checkpoint (activity) modulators in concurrent, separate orsequential combination.

In an eighth aspect of the invention, there is provided an Axlinhibitor, for use in the prevention, treatment or management of cancer,wherein the prevention, treatment or management of cancer is in apatient to whom an oncolytic virus has been or will be administered.

The prevention, treatment or management of cancer is in a patient may beto whom an immune checkpoint (activity) modulator has also been or willalso be administered.

In a ninth aspect of the invention, there is provided a method ofpreventing, treating or managing cancer in a patient to whom anoncolytic virus has been or will be administered, the method comprisingadministering to a patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor.

In this method of preventing, treating or managing cancer in a patient,an immune checkpoint (activity) modulator may also have been or willalso be administered.

In a tenth aspect of the invention, there is provided a pharmaceuticalcomposition comprising an Axl inhibitor, one or more oncolytic viruses,and a pharmaceutically acceptable excipient. The pharmaceuticalcomposition may further comprise one or more immune checkpoint(activity) modulators.

These aspects are based on the surprising observation that there is asynergistic interaction between an Axl inhibitor and one or moreoncolytic viruses (preferably in further combination with one or moreimmune checkpoint (activity) modulators, since the combinationunexpectedly reinforces checkpoint modulation), which provides asignificantly better therapeutic profile than when each agent is used inisolation, i.e. there is an effect which surpasses expecations based onadditive effects.

As will be appreciated by one skilled in the art, any of the preferredembodiments of the first aspect of the invention apply equally to any ofthe second to tenth aspects of the invention.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ radical.

“Carboxy” refers to the —C(O)OH radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms and which is attached tothe rest of the molecule by a single bond, for example, methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.For purposes of this invention, the term “lower alkyl” refers to analkyl radical having one to six carbon atoms.

“Optionally substituted alkyl” refers to an alkyl radical, as definedabove, which is optionally substituted by one or more substituentsselected from the group consisting of halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to twelve carbon atoms, preferably one toeight carbon atoms and which is attached to the rest of the molecule bya single bond, for example, ethenyl, prop-1-enyl, but-1-enyl,pent-1-enyl, and penta-1,4-dienyl.

“Optionally substituted alkenyl” refers to an alkenyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (wherep is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ where each R²⁰ is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, optionally containing at least one double bond, having fromtwo to twelve carbon atoms, preferably one to eight carbon atoms andwhich is attached to the rest of the molecule by a single bond, forexample, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

“Optionally substituted alkynyl” refers to an alkynyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (wherep is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ where each R²⁰ is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.

“Straight or branched alkylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing nounsaturation and having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, and n-butylene. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain.

“Optionally substituted straight or branched alkylene chain” refers toan alkylene chain, as defined above, which is optionally substituted byone or more substituents selected from the group consisting of halo,cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Straight or branched alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, and n-butenylene. The alkenylene chain isattached to the rest of the molecule through a double bond or a singlebond and to the radical group through a double bond or a single bond.The points of attachment of the alkenylene chain to the rest of themolecule and to the radical group can be through one carbon or any twocarbons within the chain.

“Optionally substituted straight or branched alkenylene chain” refers toan alkenylene chain, as defined above, which is optionally substitutedby one or more substituents selected from the group consisting of halo,cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Straight or branched alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, for example,propynylene, and n-butynylene. The alkynylene chain is attached to therest of the molecule through a single bond and to the radical groupthrough a double bond or a single bond. The points of attachment of thealkynylene chain to the rest of the molecule and to the radical groupcan be through one carbon or any two carbons within the chain.

“Optionally substituted straight or branched alkynylene chain” refers toan alkynylene chain, as defined above, which is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where tis 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ whereeach R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, forman optionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 14 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic, ortricyclic system and which may include spiro ring systems. An arylradical is commonly, but not necessarily, attached to the parentmolecule via an aromatic ring of the aryl radical. For purposes of thisinvention, an “aryl” radical as defined herein can not contain ringshaving more than 7 members and cannot contain rings wherein twonon-adjacent ring atoms thereof are connected through an atom or a groupof atoms (i.e., a bridged ring system). Aryl radicals include, but arenot limited to, aryl radicals derived from acenaphthylene, anthracene,azulene, benzene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene, andphenanthrene.

“Optionally substituted aryl” refers to an aryl radical, as definedabove, which is optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—O—R²²—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, each R²¹ isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R²² is a straight or branched alkylene oralkenylene chain.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl and diphenylmethyl.

“Optionally substituted aralkyl” refers to an aralkyl radical, asdefined above, wherein the alkylene chain of the aralkyl radical is anoptionally substituted alkylene chain, as defined above, and each arylradical of the aralkyl radical is an optionally substituted arylradical, as defined above.

“Aralkenyl” refers to a radical of the formula —R_(d)—R_(e) where R_(d)is an alkenylene chain as defined above and R_(e) is one or more arylradicals as defined above.

“Optionally substituted aralkenyl” refers to an aralkenyl radical, asdefined above, wherein the alkenylene chain of the aralkenyl radical isan optionally substituted alkenylene chain, as defined above, and eacharyl radical of the aralkenyl radical is an optionally substituted arylradical, as defined above.

“Aralkynyl” refers to a radical of the formula —R_(e)R_(c) where R_(e)is an alkynylene chain as defined above and R_(c) is one or more arylradicals as defined above.

“Optionally substituted aralkynyl” refers to an aralkynyl radical, asdefined above, wherein the alkynylene chain of the aralkynyl radical isan optionally substituted alkynylene chain, as defined above, and eacharyl radical of the aralkynyl radical is an optionally substituted arylradical, as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused, spiro or bridged ring systems, having from threeto fifteen carbon atoms, preferably having from three to ten carbonatoms, more preferably from five to seven carbons and which is saturatedor unsaturated and attached to the rest of the molecule by a singlebond. For purposes of this invention, a bridged ring system is a systemwherein two non-adjacent ring atoms thereof are connected through anatom or a group of atoms, wherein the atom or the group of atoms are thebridging element. An example of a bridged cycloalkyl (monovalent)radical is norbornanyl (also called bicyclo[2.2.1]heptanyl). Forpurposes of this invention, a non-bridged ring system is a system whichdoes not contain a bridging element, as described above. For purposes ofthis invention, a fused ring system is a system wherein two adjacentring atoms thereof are connected through an atom or a group of atoms. Anexample of a fused cycloalkyl (monovalent) radical isdecahydronaphthalenyl (also called decalinyl). For purposes of thisinvention, a spiro ring system is a system wherein two rings are joinedvia a single carbon (quaternary) atom. An example of a Spiro cycloalkyl(monovalent) radical is spiro[5.5]undecanyl. Monocyclic cycloalkylradicals do not include spiro, fused or bridged cycloalkyl radicals, butdo include for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals includefused, spiro or bridged cycloalkyl radicals, for example, C₁₀ radicalssuch as adamantanyl (bridged) and decalinyl (fused), and C₇ radicalssuch as bicyclo[3.2.0]heptanyl (fused), norbornanyl and norbornenyl(bridged), as well as substituted polycyclic radicals, for example,substituted C₇ radicals such as 7,7-dimethylbicyclo[2.2.1]heptanyl(bridged).

“Optionally substituted cycloalkyl” refers to a cycloalkyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R², —R²¹—N(R²⁰)₂, —R²¹—C(O)R², —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰, —R²¹—N(R²⁰)C(O)R²⁰,—R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂, —R²¹—S(O)_(t)OR²⁰ (where t is1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —R²¹—S(O)₂N(R²)₂,where each R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, forman optionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl, and each R²¹ is independently a direct bond or a straightor branched alkylene or alkenylene chain.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g), whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Optionally substituted cycloalkylalkyl” refers to a cycloalkylalkylradical, as defined above, wherein the alkylene chain of thecycloalkylalkyl radical is an optionally substituted alkylene chain, asdefined above, and the cycloalkyl radical of the cycloalkylalkyl radicalis an optionally substituted cycloalkyl radical, as defined above.

“Cycloalkylalkenyl” refers to a radical of the formula —R_(d)R_(g) whereR_(d) is an alkenylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Optionally substituted cycloalkylalkenyl” refers to a cycloalkylalkenylradical, as defined above, wherein the alkenylene chain of thecycloalkylalkenyl radical is an optionally substituted alkenylene chain,as defined above, and the cycloalkyl radical of the cycloalkylalkenylradical is an optionally substituted cycloalkyl radical as definedabove.

“Cycloalkylalkynyl” refers to a radical of the formula —R_(e)R_(g) whereR_(e) is an alkynylene radical as defined above and R_(g) is acycloalkyl radical as defined above.

“Optionally substituted cycloalkylalkynyl” refers to a cycloalkylalkynylradical, as defined above, wherein the alkynylene chain of thecycloalkylalkynyl radical is an optionally substituted alkynylene chain,as defined above, and the cycloalkyl radical of the cycloalkylalkynylradical is an optionally substituted cycloalkyl radical as definedabove.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, and1-bromomethyl-2-bromoethyl.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringsystem radical which comprises one to twelve carbon atoms and from oneto six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. Unless stated otherwise specifically in thespecification, the heterocyclyl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include spiro or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated. Examples of a bridged heterocyclyl include, but arenot limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl,diazabicyclo[3.3.1]nonanyl, diazabicyclo[3.2.2]nonanyl andoxazabicyclo[2.2.1]heptanyl. A “bridged N-heterocyclyl” is a bridgedheterocyclyl containing at least one nitrogen, but which optionallycontains up to four additional heteroatoms selected from O, N and S. Forpurposes of this invention, a non-bridged ring system is a systemwherein no two non-adjacent ring atoms thereof are connected through anatom or a group of atoms. Examples of heterocyclyl radicals include, butare not limited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl,octahydro-1H-pyrrolo[3,2-c]pyridinyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl,octahydro-1H-pyrrolo[2,3-b]pyridinyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-c]pyrrolyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, 3,7-diazabicyclo[3.3.1]nonan-3-yl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thienyl[1,3]dithianyl,trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl,octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and2,7-diazaspiro[4.4]nonanyl.

“Optionally substituted heterocyclyl” refers to a heterocyclyl radical,as defined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹is independently a direct bond or a straight or branched alkylene oralkenylene chain.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe N-heterocyclyl radical to the rest of the molecule may be through anitrogen atom in the N-heterocyclyl radical or through a carbon in theN-heterocyclyl radical.

“Optionally substituted N-heterocyclyl” refers to an N-heterocyclyl, asdefined above, which is optionally substituted by one or moresubstituents as defined above for optionally substituted heterocyclyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkyl” refers to a heterocyclylalkylradical, as defined above, wherein the alkylene chain of theheterocyclylalkyl radical is an optionally substituted alkylene chain,as defined above, and the heterocyclyl radical of the heterocyclylalkylradical is an optionally substituted heterocyclyl radical, as definedabove.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(d)R_(h)where R_(d) is an alkenylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkenylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkenyl” refers to aheterocyclylalkenyl radical, as defined above, wherein the alkenylenechain of the heterocyclylalkenyl radical is an optionally substitutedalkenylene chain, as defined above, and the heterocyclyl radical of theheterocyclylalkenyl radical is an optionally substituted heterocyclylradical, as defined above.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(e)R_(h)where R_(e) is an alkynylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkynylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkynyl” refers to aheterocyclylalkynyl radical, as defined above, wherein the alkynylenechain of the heterocyclylalkynyl radical is an optionally substitutedalkynylene chain, as defined above, and the heterocyclyl radical of theheterocyclylalkynyl radical is an optionally substituted heterocyclylradical, as defined above.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. A heteroaryl radical iscommonly, but not necessarily, attached to the parent molecule via anaromatic ring of the heteroaryl radical. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ringsystem, which may include spiro or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl radical may beoptionally oxidized and the nitrogen atom may be optionally quaternized.For purposes of this invention, the aromatic ring of the heteroarylradical need not contain a heteroatom, as long as one ring of theheteroaryl radical contains a heteroatom. For example benzo-fusedheterocyclyls such as 1,2,3,4-tetrahydroisoquinolin-7-yl are considereda “heteroaryl” for the purposes of this invention. Except for thepolycyclic heteroaryls containing more than 14 ring atoms, as definedbelow, a “heteroaryl” radical as defined herein can not contain ringshaving more than 7 members and cannot contain rings wherein twonon-adjacent members thereof are connected through an atom or a group ofatoms (i.e., a bridged ring system). Examples of heteroaryl radicalsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, benzo[b]azepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranoniyl, benzopuranyl, benzofurmnonyl,benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimiidinyl,benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,cinnolinyl, cyclopenta[d]pyrimidinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,cyclopenta[4,5]thieno[2,3-d]pyrimidinyl such as6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl,5,6-dihydrobenzo[h]cinnolinyl,7′,8′-dihydro-5′H-spiro[[1,3]dioxolane-2,6′-quinoline]-3′-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,dihydropyridooxazinyl such as 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,dihydropyridothiazinyl such as3,4-diihydro-2H-pyrido[3,2-b][1,4]thiazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,furopyrimidinyl, furopyridazinyl, furopyrazinyl, isothiazolyl,imidazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indazolyl, isoindolyl,indolinyl, isoindolinyl, isoquinolinyl (isoqjuinolyl), indolizinyl,isoxazolyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl,2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,19a-octahydrobenzo[h]quinazolinyl,3′-oxo-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]yl,7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl,pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl (pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl,pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl,2H-pyrido[3,2-b][1,4]oxazinonyl, 1H-pyrido[2,3-b][1,4]oxazinonyl,pyrrolopyridinyl such as 1H-pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimiidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl,thieno[2,3-d]pyrimidinyl, thienopyrimidinyl (e.g.,thieno[3,2-d]pyrimidinyl), thieno[2,3-c]pyridinyl, thienopyridazinyl,thienopyrazinyl, and thiophenyl (thienyl).

“Optionally substituted heteroaryl” refers to a heteroaryl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R² (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹is independently a direct bond or a straight or branched alkylene oralkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe N-heteroaryl radical to the rest of the molecule may be through anitrogen atom in the N-heteroaryl radical or through a carbon atom inthe N-heteroaryl radical.

“Optionally substituted N-heteroaryl” refers to an N-heteroaryl, asdefined above, which is optionally substituted by one or moresubstituents as defined above for optionally substituted heteroaryl.

“Polycyclic heteroaryl containing more than 14 ring atoms” refers to a15- to 20-membered ring system radical comprising hydrogen atoms, one tofourteen carbon atoms, one to eight heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur, and at least one aromaticring. A “polycyclic heteroaryl containing more than 14 ring atoms”radical is commonly, but not necessarily, attached to the parentmolecule via an aromatic ring of the “polycyclic heteroaryl containingmore than 14 ring atoms” radical. For purposes of this invention, the“polycyclic heteroaryl containing more than 14 ring atoms” radical maybe a bicyclic, tricyclic or tetracyclic ring system, which may includefused or spiro ring systems; and the nitrogen, carbon or sulfur atoms inthe “polycyclic heteroaryl containing more than 14 ring atoms” radicalmay be optionally oxidized and the nitrogen atom may also be optionallyquaternized. For purposes of this invention, the aromatic ring of the“polycyclic heteroaryl containing more than 14 ring atoms” radical neednot contain a heteroatom, as long as one ring of the “polycyclicheteroaryl containing more than 14 ring atoms” radical contains aheteroatom. Examples of “polycyclic heteroaryl containing more than 14ring atoms” radicals include, but are not limited to,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yland 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl.

“Optionally substituted polycyclic heteroaryl containing more than 14ring atoms” is meant to include “polycyclic heteroaryl containing morethan 14 ring atoms” radicals, as defined above, which are optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰,—R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²—C(O)N(R²⁰)₂,—R²¹—N(R²⁰)C(O)OR²⁰, —R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)_(t)R²⁰ (where tis 1 or 2), —R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰(where p is 0, 1 or 2), and —R²¹—S(O)_(t)N(R²⁰)₂ (where t is 1 or 2),where each R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, mayoptionally form an optionally substituted N-heterocyclyl or anoptionally substituted N-heteroaryl, and each R²¹ is independently adirect bond or a straight or branched alkylene or alkenylene chain.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkyl” refers to a heteroarylalkylradical, as defined above, wherein the alkylene chain of theheteroarylalkyl radical is an optionally substituted alkylene chain, asdefined above, and the heteroaryl radical of the heteroarylalkyl radicalis an optionally substituted heteroaryl radical, as defined above.

“Heteroarylalkenyl” refers to a radical of the formula —R_(d)R_(i) whereR_(d) is an alkenylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkenylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkenyl” refers to a heteroarylalkenylradical, as defined above, wherein the alkenylene chain of theheteroarylalkenyl radical is an optionally substituted alkenylene chain,as defined above, and the heteroaryl radical of the heteroarylalkenylradical is an optionally substituted heteroaryl radical, as definedabove.

“Heteroarylalkynyl” refers to a radical of the formula —R_(e)R_(i) whereR_(e) is an alkynylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkynylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkynyl” refers to a heteroarylalkynylradical, as defined above, wherein the alkynylene chain of theheteroarylalkynyl radical is an optionally substituted alkynylene chain,as defined above, and the heteroaryl radical of the heteroarylalkynylradical is an optionally substituted heteroaryl radical, as definedabove.

“Hydroxyalkyl” refers to an alkyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Patient” means a mammal who has been diagnosed as having cancer and/ormetastatic cancer, or who is predisposed to having metastatic cancer dueto having cancer.

“Mammal” means any vertebrate of the class Mammalia. Humans and domesticanimals, such as cats, dogs, swine, cattle, sheep, goats, horses,rabbits, and the like are a particular focus. Preferably, for purposesof this invention, the mammal is a primate (e.g., monkey, baboon,chimpanzee and human), and more preferably, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventor circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. However, when a first functional group is described as“optionally substituted,” and in turn, substituents on the firstfunctional group are also “optionally substituted” and so forth, for thepurposes of this invention, such iterations for a radical to beoptionally substituted are limited to three. Thus, groups described assubstituents on the third iteration are not themselves optionallysubstituted. For example, if an R group herein is defined as being“optionally substituted aryl” (the first iteration) and the optionalsubstituents for the “optionally substituted aryl” include “optionallysubstituted heteroaryl” (the second iteration) and the optionalsubstituents for the “optionally substituted heteroaryl” include“optionally substituted cycloalkyl” (the third iteration), the optionalsubstituents on the cycloalkyl can not be optionally substituted.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by a regulatory body (e.g. theUnited States Food and Drug Administration) as being acceptable for usein humans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, and undecylenic acid.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferredinorganic salts are the ammonium, sodium, potassium, calcium, andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

An “anti-Axl antibody” refers to an antibody which provides inhibitionof Axl activity.

Preferably, the anti-Axl antibody is an antibody as described in any ofthe following references: UK patent application 1422605.4, internationalpatent application PCT/EP2015/063700, international patent applicationPCT/EP2015/063704, European patent publication EP2267454, internationalpatent publication WO 2009063965, international patent publication WO2011159980, European patent publication EP2228392, international patentpublication WO 2012175691, international patent publication WO2012175692, international patent publication WO 2009062690, andinternational patent publication WO 2010130751 (the contents of each ofwhich is hereby incorporated by reference).

For example, in one embodiment, the anti-Axl antibody is an antibody asdescribed in UK patent application 1422605.4, the contents of which ishereby incorporated by reference, particularly as shown at pages 93-96.

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent application PCT/EP2015/063700, the contents ofwhich is hereby incorporated by reference, particularly as shown atpages 82-83.

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent application PCT/EP2015/063704, the contents ofwhich is hereby incorporated by reference, particularly as shown atpages 72-73.

In another embodiment, the anti-Axl antibody is an antibody as describedin European patent publication EP2267454, the contents of which ishereby incorporated by reference.

In another embodiment, the anti-Axl antibody is an antibody as describedin European patent publication EP 2228392A1, the contents of which ishereby incorporated by reference, particularly as shown at pages 31-33.

In another embodiment, the anti-Axl antibody is an antibody as describedin US patent publication US 2012/0121587 A1, the contents of which ishereby incorporated by reference, particularly as shown at pages 26-61.

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent publication WO 2011159980, the contents of whichis hereby incorporated by reference, particularly as shown in FIG. 2 ,Figure page 6 (of 24).

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent publication WO 2012175691, the contents of whichis hereby incorporated by reference, particularly as shown at page 5.

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent publication WO 2012175692, the contents of whichis hereby incorporated by reference, particularly as shown at pages 4-5.

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent publication WO 2009062690, the contents of whichis hereby incorporated by reference.

In another embodiment, the anti-Axl antibody is an antibody as describedin international patent publication WO 2010130751, the contents of whichis hereby incorporated by reference, particularly as shown at Figurepages 1-17 (of 78).

Preferably, the anti-Axl antibody is an antibody as described in UKpatent application 1422605.4, international patent applicationPCT/EP2015/063700, international patent application PCT/EP2015/063704,or international patent publication WO 2011159980.

An “oncolytic virus” refers to a virus that preferentially infects andlyses cancer or tumour cells as compared to normal cells.Cytotoxic/oncolytic activity of the virus may be present, observed ordemonstrated in vitro, in vivo, or both. Preferably, the virus exhibitscytotoxic/oncolytic activity in vivo.

The oncolytic virus includes virsues with natural tumour selection suchas reovirus, Newcastle disease virus (NDV), adenovirus, herpes virus(e.g. herpes simplex 1), polio virus, mumps virus, measles virus,influenza virus, vaccinia virus, rhabdovirus, parvovirus, vesicularstomatitis virus, and derivatives and variants thereof whichpreferentially infect and lyse cancer or tumour cells as compared tonormal cells, preferably Newcastle disease virus, reovirus, autonomousparvovirus, vesicular stomatitis virus, and herpes simplex 1 virus, andderivatives and variants thereof. Particularly, Newcastle disease virus,reovirus, autonomous parvovirus and vesicular stomatitis virus, asdescribed in Everts et al. Cancer Gene Therapy, 2005, 12, 141-161, andshown in Table A (preferably Newcastle disease virus).

TABLE A Genetic/phenotypic Virus Class, Subclass target within tumorsNDV ssRNA⁻, rhabdovirus Activated ras-pathway; defective IFN-pathwayReovirus dsRNA, reovirus Activated ras-pathway Autonomous ssDNA,parvovirus IFN-resistance of tumors parvovirus VSV ssRNA⁻, rhabdovirusLoss of cell cycle control? NDV, Newcastle disease virus; VSV, vesicularstomatitis virus; IFN, interferon; ds, double stranded; ss,single-stranded; ssRNA, RNA as a template for mRNA.

The oncolytic virus also includes virsues with gene deletions to achievetumour-selective replication, as shown in Table B, and viruses producedusing tissue- and tumour-specific promoters for tumour-selectivereplication, as shown in Table C (as described in Everts et al. CancerGene Therapy, 2005, 12, 141-161).

TABLE B Parental Genetic/phenotypic strain Agent Genetic alterationtarget within tumours Adenovirus ONYX-015 E1B-55kd deletion p53null/mutant or/and inactivated p53-pathway Ad-A24 E1A CR2 deletion pRbnull/mutant or/and loss of cell cycle control CB-1 E1A CR2 deletion; pRband p53 defective E1B-55kd deletion pathways errand loss of cell cyclecontrol d22-947 E1A CR2 deletion pRb null/mutant or/and loss of cellcycle control dl331 VA-I gene deletion Ras-activated pathway Herpesdlsptk Thymidine kinase Replication simplex gene deletion virus-1 R3616Delation of both Loss of γ34.5 genes neurovirulence HrR3 ICP6 genedeletion Replication G207 Deletion of both Replication; γ34.5 genes;loss of ribonucleotide neurovirulence reductase disruption NV1020Deletion of one Replication, γ34.5 gene; loss of delation in tkneurovirulence gene; insertion of exogenous copy of tk gene VacciniaVV-TK Thymidine kinase Replication virus gene deletion VV-SPI-1/2Deletion of Replication SPI-1 and SPI-2 genes WDD Thymidine Replicationkinase gene deletion; deletion of VGF gene Polio virus PV1(RIPO) IRESelement Loss of replaced by neurovirulence; IRES from HRV2 replicationInfluenza IVA-NS1 NS1 gene IFN-pathway virus deletion deficiency tk,thymidine kinase: IRES, internal ribosomal entry site; HRV2, humanrhinovirus type 2: IFN, interferon.

TABLE C Promoter Tissue-tumour type Applied virus Osteocalcin promoterOsteosarcoma Adenovirus PSA promoter Prostate Adenovirus AFP promoterHepatocellular Adenovirus carcinoma Tyrosinase promoter MelanocytesAdenovirus MUC-1 promoter Breast carcinomas Adenovirus HSV-1 Midkinedifferentation Neuroblastoma Adenovirus factor promoter Rat probasinpromoter Prostate Adenovirus Leukoprotease inhibitor Ovarian carcinomaAdenovirus promoter Tcf responsive promoter Colon cancer AdenovirusAutonomous parvovirus Calponin promoter Smooth muscle cells HSV-1Albumin enhancer-promoter Liver HSV-1 Flt-1 promoter TeratocarcinomaAdenovirus E2F-1 promoter Cancer cells in Adenovirus general Telomerasereverse Cancer cells in Adenovirus transcriptase promoter generalHypoxia responsive Cancer cells in Adenovirus elements general PSA,prostate-specific antigen; AFP, α-fetoprotein; Flt-1, vascularendothelial growth factor receptor type 1; HSV-1, herpes simplexvirus-1.

A “derivative” or “variant” of a virus refers to a virus (i) obtained byselecting the virus under different growth conditions, (ii) one that hasbeen subjected to a range of selection pressures, (iii) one that hasbeen genetically modified using recombinant techniques known in the art,or any combination thereof.

Possible strategies to improve the intrinsic anti-tumour potency ofoncolytic viruses are as described in Everts et al. Cancer Gene Therapy,2005, 12, 141-161, and shown in Table D.

TABLE D Applied virus Strategy Example Way of action (inserted gene) 1.Insertion Expression of Increase of Adenovirus of genes adenoviral E3viral-induced (E3) encoding gene coding for cell lysis cytotoxicadenoviral proteins death protein Expression of Increase of Adenovirussyncytium- cell killing (FMG) inducing of both genes infected and HSV-1(FMG) uninfected cells through syncytium induction Deletion of Moreefficient Adenovirus apoptosis cell killing by (—) inhibitorviral-induced EfB-19kd apoptosis protein 2. Elicitation ExpressionActivation and HSV-1 (IL-4) of an of cytokine stimulation of antitumorgenes tumor-specific immune cytotoxic response T cells Use ofElicitation HSV-1 (IL-12) oncolysates. of an immune Vaccinia virustreatment response (GM-CSF) Vaccinia with virus- directed virus (IL-2)augmented against Parvovirus (MCP-1) tumor cells tumor-specificAdenovirus (IFN) antigens Vaccinia virus (—) VSV (—) NDV (−) ExpressionElicitation Vaccinia virus of tumor- of an immune (CEA) Vacciniaspecific response virus (PSA) antigens directed against tumor-specificantigens GM-CSF, granulocyte-macrophage colony-stimulating factor;MCP-1, monocyte chemotactic protein 1, FMG, fusogenic membraneglycoprotein; IL, interleukin, CEA, carcinoembryonic antigen.

Specific examples of NDV variants are as described in WO2014/158811,particularly pages 3-10, i.e., Newcastle disease viruses engineered toexpress an agonist of a co-stimulatory signal of an immune cell. Afurther specific variant includes a herpes simplex 1 variant known asoncolytic immunotherapy talimogene laherparepvec (T-VEC), which isengineered through the genetic alteration of the herpes simplex 1 virusto secrete the cytokine GM-CSF within the tumour, causing cell lysis.

A “pharmaceutical composition” refers to a formulation of an Axlinhibitor (preferably a compound of formula (I)) and/or a formulation ofan immune checkpoint (activity) modulator and a medium generallyaccepted in the art for the delivery of the biologically active compoundto mammals, for example, humans. Such a medium includes allpharmaceutically acceptable carriers, diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of thetherapeutic agent sufficient to destroy, modify, control or removecancer tissue. A therapeutically effective amount may refer to theamount of therapeutic agents sufficient to delay or minimise the spreadof cancer. A therapeutically effective amount may also refer to theamount of the therapeutic agent that provides a therapeutic benefit inthe treatment or management of cancer. Further, a therapeuticallyeffective amount with respect to an Axl inhibitor of the combinationtherapies of the invention means that amount of an Axl inhibitor incombination with one or more immune checkpoint (activity) modulatorsthat provides a therapeutic benefit in the treatment or management ofcancer, including the amelioration of symptoms associated with cancer.Used in connection with an amount of an Axl inhibitor, the term canencompass an amount that improves overall therapy, reduces or avoidsunwanted effects, or enhances the therapeutic efficacy of and synergiseswith the one or more immune checkpoint (activity) modulators utilised inthe combination therapies of the invention.

“Prophylactically effective amount” refers to that amount of theprophylactic agent sufficient to result in the prevention of cancer. Aprophylactically effective amount may refer to the amount ofprophylactic agent sufficient to prevent cancer in a patient, including,but not limited to, those patients who are predisposed to cancer orpreviously exposed to carcinogens. A prophylactically effective amountmay also refer to the amount of the prophylactic agent that provides aprophylactic benefit in the prevention of cancer. Further, aprophylactically effective amount with respect to an Axl inhibitor ofthe combination therapies of the invention means that amount of an Axlinhibitor in combination with one or more immune checkpoint (activity)modulators that provides a prophylactic benefit in the prevention ofcancer. Used in connection with an amount of an Axl inhibitor, the termcan encompass an amount that improves overall prophylaxis or enhancesthe prophylactic efficacy of and synergises with the one or more immunecheckpoint (activity) modulators.

As used herein, the terms “manage”, “managing” and “management” refer tothe beneficial effects that a patient derives from a combination therapyof the invention, which does not result in a cure of the cancer. Incertain embodiments, a combination therapy of the invention “manages”metastatic cancer so as to prevent the progression or worsening of thecancer.

As used herein, the terms “prevent”, preventing” and “prevention” referto the prevention of the spread or onset of cancer in a patient.

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication, removal, modification or control of cancer that resultsfrom the combination therapy of the invention. In certain embodiments,such terms refer to the minimizing or delay of the spread of cancer.

The compounds of formula (I), or their pharmaceutically acceptablesalts, may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

“Atropisomers” are stereoisomers resulting from hindered rotation aboutsingle bonds where the barrier to rotation is high enough to allow forthe isolation of the conformers (Eliel, E. L.; Wilen, S. H.Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994;Chapter 14). Atropisomerism is significant because it introduces anelement of chirality in the absence of stereogenic atoms. The inventionis meant to encompass atropisomers, for example in cases of limitedrotation around the single bonds emanating from the core triazolestructure, atropisomers are also possible and are also specificallyincluded in the compounds of the invention.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds of formula (I) are named herein as derivatives of the centralcore structure, i.e., the triazole structure. For complex chemical namesemployed herein, a substituent group is named before the group to whichit attaches. For example, cyclopropylethyl comprises an ethyl backbonewith cyclopropyl substituent. In chemical structure diagrams, all bondsare identified, except for some carbon atoms, which are assumed to bebonded to sufficient hydrogen atoms to complete the valency.

For purposes of this invention, the depiction of the bond attaching theR³ substituent to the parent triazole moiety in formula (I), as shownbelow:

is intended to include only the two regioisomers shown below, i.e.,compounds of formula (Ia) and (Ib):

The numbering system of the ring atoms in compounds of formula (Ia) isshown below:

For example, a compound of formula (Ia) wherein R¹, R⁴ and R⁵ are eachhydrogen, R² is 4-(2-(pyrrolidin-1-yl)ethoxy)phenyl and R³ is6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl; i.e., acompound of the following formula:

is named herein as1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

The numbering system of the ring atoms in compounds of formula (Ib) isshown below:

Compounds of formula (Ib) are similarly named herein.

Of the various aspects of the invention, as set forth herein, certainembodiments are preferred.

In one preferred embodiment of the use of the present invention, thecompound of formula (I) is a compound of formula (Ia):

wherein R¹, R², R³, R⁴ and R⁵ are as described above for compounds offormula (I), as an isolated stereoisomer or mixture thereof or as atautomer or mixture thereof, or a pharmaceutically acceptable salt orN-oxide thereof.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above, R² and R³ are each independently a polycyclicheteroaryl containing more than 14 ring atoms optionally substituted byone or more substituents selected from the group consisting of oxo,thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸,—R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN, —R⁹—O—R¹⁰—C(O)OR⁸,—R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2),—R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷,—R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹²,—R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2),—R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and R¹, R⁴, R⁵, eachR⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹ and R¹² are asdescribed above for compounds of formula (Ia).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; and each R¹¹ is independently selected from the group    consisting of hydrogen, alkyl, cyano, nitro and —OR⁸.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² and R³ are each independently a polycyclic heteroaryl containing    more than 14 ring atoms selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use wherein the compound of formula (Ia) is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(5′,5′-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above, R² is a polycyclic heteroaryl containing more than 14ring atoms optionally substituted by one or more substituents selectedfrom the group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,alkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,—R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where pis 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,—R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,—R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ is selected fromthe group consisting of aryl and heteroaryl, where the aryl and theheteroaryl are each independently optionally substituted by one or moresubstitutents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹²,—R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹²,—R¹³—C(O)OR¹², —R¹³—C(O)N(R²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,—R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,—R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where tis 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and—R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); and R¹, R⁴, R⁵, each R⁶, eachR⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹, each R¹², each R¹³ and eachR¹⁴ are as described above for compounds of formula (Ia).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl, or two R¹²'s, together with the common nitrogen to    which they are both attached, form an optionally substituted    N-heterocyclyl or an optionally substituted N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   R² is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-1-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)—OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroerylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl, or two R²'s, together with the common nitrogen to    which they are both attached, form an optionally substituted    N-heterocyclyl or an optionally substituted N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is a use where, in the compound of formula (Ia) asset forth above:

-   R² is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)—OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and-   R³ is heteroaryl selected from the group consisting of pyridinyl,    pyrimidinyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl,    benzo[d]imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl,    thieno[3,2-d]pyrimidinyl and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R²)₂,    —R¹³—C(O)N(R²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(p)R¹²    (where t is 1 or 2), —R¹³—S(O)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2).

Another embodiment is a use wherein the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dimethoxy-quinazolin-4-yl)-N³-(5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N³-(5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N³-(5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N³-(5′,5′-dimethyl-6,8,9,10-9tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above, R² is selected from the group consisting of aryl andheteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substitutents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); R³is a polycyclic heteroaryl containing more than 14 ring atoms optionallysubstituted by one or more substituents selected from the groupconsisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,—R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where pis 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,—R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,—R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and R¹, R⁴, R⁵, eachR⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹, each R¹², each R¹³and each R¹⁴ are as described above for compounds of formula (I).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,    —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R¹²'s, together with the    common nitrogen to which they are both attached, form an optionally    substituted N-heterocyclyl or an optionally substituted    N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is aryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R⁸)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹³—N(R²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is aryl selected from the group consisting of phenyl and    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹³—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)OR¹² (where t    is 1 or 2), —R¹—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹³—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)₁N(R¹²)₂ (where t is 1 or 2).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    and optionally substituted heterocyclyl where the optionally    substituted heterocyclyl is selected from the group consisting of    piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,    decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,    azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,    octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and    azetidinyl; each independently optionally substituted by one or two    substituents selected from the group consisting of —R⁹—OR⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)OR⁶, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)R⁷,    —R⁹—N(R⁶)C(O)OR⁸, alkyl, halo, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   N³-(4-(4-cyclohexanylpiperazin-1-yl)phenyl)-1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-methyl-3-phenylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-(4-(4    piperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(indolin-2-on-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(morpholin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-cyclopentyl-2-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-cyanophenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-(diethylamino)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-10-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-10-fluorobenzo[6,7]cyclohepta[1,2c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(cyclohexyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(cyclohexyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-dimethylaminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-chloro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-trifluoromethyl-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9,10-dimethoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9,10,11-trimethoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(5-methyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-pyrrolidin-1-yl-azepan-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-N³-methylpiperidin-4-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-(pyrrolidinyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(5-propyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(decahydropyrazino[1,2-a]azepin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(5-cyclopentyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-(pyrrolidin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-yl-azepan-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(1-methyloctahydropyrrolo[3,4-b]pyrrol-5-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(N-methylcyclopentylamino)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(dipropylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(1-propyloctahydro-1H-pyrrolo[3,2-c]pyridine-5-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-(N-methylpiperazin-1l-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(tert-butyloxycarbonylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-aminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(5-cyclohexyloctahydropyrrolo[3,4-c]pyrrolyl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-NM-(4-(methylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-methyl-4-(4-pyrrolidin-1-yl    piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclopentylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-N³-methylpiperidin-4-ylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(N-isopropylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-pyrrolidin-1-ylazetidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-methyl-4-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2c]pyridazin-3-yl)-N³-(3-fluoro-4-((S)-3-(pyrrolidin-1-ylmethyl)pyrrolidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidinylmethyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-((4aR,8aS)-decahydroisoquinolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(octahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-(4-(3-pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(5-methyloctahydropyrrolo[3,4-c]pyrrolyl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(octahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-9-chloro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-9-chloro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(N-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-iodophenyl)-1-1,2,4-triazole-3,5-diamine;-   1-(spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-(3R)-dimethylaminopyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-methyl-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N³-(3-fluoro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N³-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(1-bicyclo[2.2.1]heptan-2-yl)-piperidin-4-ylphenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(1-cyclopropylmethylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(4-(1-bicyclo[2.2.1]heptan-2-yl)-piperidin-4-ylphenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-NM-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine,    and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of halo, alkyl,    heterocyclylalkenyl, —R¹³—OR¹², —R¹³—O—R¹³—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹²,    —R¹³—C(O)N(R¹²)₂, and —R¹³—N(R¹²)C(O)R²;-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(cyclopentyl)piperazin-1-ylcarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-pyrrolidin-1-ylethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxyphenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-(dimethylamino)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-(methoxy)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-(pyrrolidin-1-yl)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-10-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-(N-methylcyclopentylamino)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(N-methylpiperidin-4-yl-N³-methylamino)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((N-butyl-N³-acetoamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(piperidin-1-yl)piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(pyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(3-dimethylaminopyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(3-diethylaminopyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-methylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-isopropylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazola-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-cyclopentylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl-(4-(morpholin-4-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(1-methylpiperidin-3-yl-oxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    and optionally substituted heterocyclyl where the optionally    substituted heterocyclyl is selected from the group consisting of    piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,    decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,    azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,    octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and    azetidinyl; each independently optionally substituted by one or two    substituents selected from the group consisting of —R⁹—OR⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)OR⁶, —R—C(O)N(R⁶)R⁷, —R⁹—N(R′)C(O)R⁷,    —R⁹—N(R⁶)C(O)OR⁷, alkyl, halo, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N³-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N³-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(3-fluoro-4-(4-cyclohexylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(4-(4-(2S)-bicyclo[2.2.1]heptan-2-yl)-piperazinylphenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of halo, alkyl,    heterocyclylalkenyl, —R¹³—OR¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R²)—R¹⁴—N(R²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)N(R¹²)₂,    and —R¹³—N(R¹²)C(O)R¹²; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    and optionally substituted heterocyclyl where the optionally    substituted heterocyclyl is selected from the group consisting of    piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,    decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,    azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,    octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and    azetidinyl; each independently optionally substituted by one or two    substituents selected from the group consisting of —R⁹—OR⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)R⁷,    —R⁹—N(R⁶)C(O)OR⁷, alkyl, halo, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, and    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N³-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclohexylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N³-(4-(4-N³-methylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-((Z)-dibenzo[b,f][,4]thiazepin-11-yl)-N³-(3-fluoro-4-(4-diethylaminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-1H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-NM-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidinylmethyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-((4aR,8aS)-decahydroisoquinolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(octahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of halo, alkyl,    heterocyclylalkenyl, —R¹³—OR¹², —R¹³—O—R¹³—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹²,    —R¹³—C(O)N(R¹²)₂, and —R¹³—N(R¹²)C(O)R¹²; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, and    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-((Z)-dibenzo[b,f][,4]thiazepin-11-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by a substitutent selected from    the group consisting of optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl and    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2)-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; and-   R¹² is independently selected from the group consisting of hydrogen,    alkyl, haloalkyl, alkenyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl and optionally substituted heteroarylalkyl.

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((5-fluoroindolin-2-on-3-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-pyrrolidin-1-ylpiperidinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-cyclopentylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-isopropylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(isoindolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl, —R³—OR¹²,    —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R⁴—N(R²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(t)R² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and each R⁶, each R⁷, each    R⁸, each R⁹, each R¹², each R¹³ and each R¹⁴ are as described above    for compounds of formula (Ia).

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)(methyl)amino)    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-diethylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclopentylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(2-(S)-methyloxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(2-(S)-carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(8-diethylaminoethyl-9hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(S-fluoropyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(S)-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(R)-hydroxypyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl-N³-(7-(2-(R)-methylpyrrolidin-1-yl)-6,7,8,9-tetrabydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(S)-hydroxypyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(R)-fluoropyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclohexylamino    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclopropylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-tetrahydrofuran-2-ylmethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclobutylamino-6,7,8,9-tetrabydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(cyclopropylmethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(diethylamino)ethyl)methylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-pyrrolidin-1-ylpiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(piperidin-1-ylmethyl)piperidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(dimethylamino)ethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(carboxymethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrabydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycabonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl-1H-1,2,4    triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9tetrahydro-1H-benzo[7]annulene-2-yl-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-1H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((78)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9    tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-pyrido[2′,3′:    6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is heteroaryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹³—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2),-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸    (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,    —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR¹²,    —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(p)OR⁸ (where p is    1 or 2), —R⁹—S(O)_(t)R⁸ (where t is 0, 1 or 2); and each R⁶, each    R⁷, each R⁸, each R⁹, each R¹², each R¹³ and each R¹⁴ are as    described above for compounds of formula (Ia); and-   each R⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹, each R¹²,    each R¹³ and each R¹⁴ are as described above for compounds of    formula (Ia).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is heteroaryl selected from the group consisting of pyridinyl,    pyrimidinyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)n-8-yl,    benzo[d]imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R², —R¹³—N(R¹²)S(O)^(t)R¹²    (where t is 1 or 2), —R¹³—S(O)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f[1,4]thiazepin-1 l-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro(cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro(cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R² is selected from the group consisting of pyridinyl and    pyrimidinyl, each optionally substituted by one or more    substitutents selected from the group consisting of alkyl, alkenyl,    alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,    cyano, nitro, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted cycloalkylalkenyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹³—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2).

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-cyclopentyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N^(J)-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(6-aminopyridin-3-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-aminophenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-cyanophenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(benzo[d][1,3]dioxole-6-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-methylsulfonamidylphenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(2-diethylaminomethyl)pyrrolidin-1-yl)pyridin-3-yl)-N³-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-diethylaminopyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5-methylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-piperidin-1-yl-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(bicyclo[2.2.1]heptan-2-yl)-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-piperidin-1-yl)-propanylpyridin-3-yl)-11-1,2,4triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)    N³-(6-(3-(4-(piperidin-1-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-dimethylaminopiperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazol-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(4-pyrolidin-1-yl)piperidin-1-yl)pyrimidin-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(4-(piperidin-1-ylmethyl)piperidin-1-yl)pyrimidin-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-((4-piperidin-1-ylpiperidin-1-yl)carbonyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(4-cyclopropylmethylpiperazin-1-yl)pyridine-5-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(3-(S)-methyl-4-cyclopropylmethylpiperazin-1-yl)pyridine-5-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ia) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is selected from the group consisting of    4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl, benzo[d]imidazolyl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-1-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro(cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro(cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where the compound of formula (Ia), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-S-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(dimethylaminomethyl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclopentyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-methylpiperazin-1-yl)carbonyl-5,6,7,8-tetrahydroquinolin-3-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #31, 1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)-1H-1,2,4-triazole-3,5-diamino;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3,4-dihydro-2H-benzo[b,f[1,4]dioxepin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(2-(pyrrolidin-1-ylmethyl)benzo(d]oxazol-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-dimethylaminoethyl)-(3,4-dihydro-2H-benzo[b,f][1,4]oxazin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(4-(2-dimethylaminoethyl)-(3,4-dihydro-2H-benzo[b,f][1,4]oxazin-7-yl))-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(2-(I-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)oxomethyl)benzo[b]thiophen-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-cyclopentyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-cyclopentyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-cyclopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³—((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where the compound of formula (Ia), as setforth above, is a compound of formula (Ia1):

wherein:

-   A is ═C(H)— or ═N—;-   each R^(2a) is independently selected from the group consisting of    —N(R^(12a))₂ and —N(R^(12a))C(O)R^(12a),-   or R^(2a) is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R²¹—C(O)OR²⁰,-   each R^(12a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R²⁰ is independently selected from the group consisting of hydrogen,    alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl; and-   R²¹ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment is wherein the compound of formula (I) is a compoundof formula (Ib):

wherein R¹, R², R³, R⁴ and R⁵ are as described above for compounds offormula (I), as an isolated stereoisomer or mixture thereof or as atautomer or mixture thereof, or a pharmaceutically acceptable salt orN-oxide thereof.

Another embodiment is the use where, in the compound of formula (Ib) asset forth above, R² and R³ are each independently a polycyclicheteroaryl containing more than 14 ring atoms optionally substituted byone or more substituents selected from the group consisting of oxo,thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸,—R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷,—R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷,—R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,—R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸,—R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is 1or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2); and R¹, R⁴, R⁵, each R⁶, each R⁷, each R⁸, each R⁹,each R¹⁰, each R¹¹ and R¹² are as described above in relation to formula(I).

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; and-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸.

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R² and R³ are each independently a polycyclic heteroaryl containing    more than 14 ring atoms selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2)

Another embodiment is the use where the compound of formula (Ib), as setforth above, is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R² is selected from the group consisting of aryl and heteroaryl,    where the aryl and the heteroaryl are each independently optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR²,    —R¹³—N(R¹²)C(O)OR², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸    (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,    —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,    —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is    1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where    p is 0, 1 or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl, or two R¹²'s, together with the common nitrogen to    which they are both attached, form an optionally substituted    N-heterocyclyl or an optionally substituted N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R² is aryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹⁴—N(R¹²)₂,    —R³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)R¹² (where t    is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²    (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R²)₂ (where t is 1 or 2);    and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸    (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,    —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR¹²,    —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(p)OR⁸ (where p is    1 or 2), —R⁹—S(O)_(t)R⁸ (where t is 0, 1 or 2);

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is aryl selected from the group consisting of phenyl and    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-1 l-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)N(R¹²)₂ (where t    is 1 or 2).

Another embodiment is the use where the compound of formula (Ib), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-(indolin-2-on-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-(morpholin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N⁵-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((5-fluoroindolin-2-on-3-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((4-pyrrolidin-1-ylpiperidinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((4-cyclopentylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((4-isopropylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-N-methylpiperid-4-ylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(3-pyrrolidin-1-ylazetidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-methyl-4-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N⁵-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-(4-(3-pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R¹, R⁴ and R are each independently hydrogen;-   R² is 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c)pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro(benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where the compound of formula (Ib), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-((bicyclo[2.2.1]heptan-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is heteroaryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹²—C(O)N(R²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(t)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)₁N(R²)₂ (where    t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸    (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,    —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,    —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is    1 or 2), —R⁹—S(O)_(p)OR⁸ (where p is 1 or 2), —R⁹—S(O)_(t)R⁸ (where    t is 0, 1 or 2);

Another embodiment is the use where, in the compound of formula (Ib) asset forth above:

-   R² is heteroaryl selected from the group consisting of pyridinyl,    pyrimidinyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl,    benzo[d]imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)R¹² (where t    is 1 or 2), —R¹³—S(O)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²    (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or    2), and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the use where the compound of formula (Ib), as setforth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(6-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5-methylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the use where the compound of formula (Ib), as setforth above, is a compound of formula (Ib 1):

wherein:

-   A is ═C(H)— or ═N—;    -   each R^(2a) is independently selected from the group consisting        of —N(R^(12a))₂ and —N(R^(12a))C(O)R^(12a),-   or R^(2a) is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R²¹—C(O)OR²⁰,-   each R^(12a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R²⁰ is independently selected from the group consisting of hydrogen,    alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl; and-   R²¹ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Preferably, the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

In one embodiment of the use in preventing, treating or managing cancerin a patient, the one or more immune checkpoint (activity) modulatorsare selected from the group consisting of anti-CTLA-4 antibodies,anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-4-1BB antibodies,anti-OX-40 antibodies, anti-GITR antibodies, anti-CD27 antibodies,anti-CD28 antibodies, anti-CD40 antibodies, anti-LAG3 antibodies,anti-ICOS antibodies, anti-TWEAKR antibodies, anti-HVEM antibodies,anti-TIM-1 antibodies, anti-TIM-3 antibodies, anti-VISTA antibodies, andanti-TIGIT antibodies.

Preferably, the one or more immune checkpoint (activity) modulators areselected from the group consisting of anti-CTLA-4 antibodies, anti-PD-1antibodies, anti-PD-L1 antibodies, anti-4-1BB antibodies, anti-OX-40antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD40antibodies, and anti-LAG3 antibodies.

For example, specific immune checkpoint (activity) modulators includeipilimumab, tremelimumab, pembrolizumab, nivolumab, and urelumab, andthose which can be identified by the drug candidate identifliorsAMP-514/MEDIO680 (MedImmune/AstraZeneca), MPDL3280A (Genentech/Roche),MEDI4736 (Medlmmune/AstraZeneca), MSB0010718C (EMD Serono), BMS-936559(Bristol-Myers Squibb), PF-05082566 (Pfizer), MEDI6469(Medlmmune/AstraZeneca), MEDI6383 (rOX40L; Medlmmune/AstraZeneca),MOXR0916 (Genentech/Roche), TRX518 (Tolerx), CDX-1127 (Celldex),CP-870,893 (Genentech/Roche), and BMS-986016 (Bristol-Myers Squibb)(preferably ipilimumab, tremelimumab, pembrolizumab, and nivolumab).

In a preferred embodiment, one or more of the immune checkpoint(activity) modulators is an immune checkpoint inhibitor, i.e. an agentwhich acts at T cell co-inhibitory receptors, such as CTLA-4, PD-1,PD-L1, BTLA, TIM-3, VISTA, LAG-3, and TIGIT.

In an alternative preferred embodiment, one or more of the immunecheckpoint (activity) modulators is an agent which acts at T cellco-stimulatory receptors, such as CD28, ICOS, 4-1BB, OX40, GITR, CD27,TWEAKR, HVEM, and TIM-1.

In another alternative preferred embodiment, one or more of the immunecheckpoint (activity) modulators is an agent which acts at dendriticcell co-stimulatory receptors, such as CD40 and 4-1BB.

In a particularly preferred embodiment of the invention, two or moreimmune checkpoint (activity) modulators are employed in conjunction withthe Axl inhibitor. Results have shown that an improved synergisticeffect can be obtained when at least two different immune checkpoint(activity) modulators are employed, especially when such immunecheckpoint (activity) modulators act at different cell receptorsub-types. For example, the combination of at least one immunecheckpoint inhibitor and at least one T cell co-stimulatory receptoragonist or dendritic cell co-stimulatory receptor agonist.

Preferably, at least one of the two immune checkpoint (activity)modulators is an anti-CTLA-4 antibody or an anti-PD-1 antibody. Inparticular, the combination of an anti-CTLA-4 antibody and an anti-PD-1antibody has proven to be particularly effective.

In terms of administration, the Axl inhibitor may be administered to thepatient, preferably a human, in an amount of between about 1 mg/kg andabout 100 mg/kg twice a day, preferably between about 5 mg/kg and about80 mg/kg twice a day, even more preferably between about 5 mg/kg andabout 25 mg/kg twice a day, and the chemotherapeutic agent isadministered to the mammal in an amount of between about 1.0 mg/kg andabout 10.0 mg/kg once a week, preferably between about 1.0 mg/kg andabout 5 mg/kg once a week, even more preferably between about 1.0 mg/kgand 2.0 mg/kg once a week.

In the combination therapies of the invention, an Axl inhibitor is usedas an active ingredient in combination with one or more immunecheckpoint (activity) modulators in the prevention, treatment ormanagement of one or more cancers. The term “combination therapy”includes simultaneous or sequential administration of the Axl inhibitorand the one or more immune checkpoint (activity) modulators, in anyorder, such as administering the Axl inhibitor at the same time as theadministration of the one or more immune checkpoint (activity)modulators, before the administration of the one or more immunecheckpoint (activity) modulators or after the administration of the oneor more immune checkpoint (activity) modulators (preferably, the Axlinhibitor is administered before the one or more immune checkpoint(activity) modulators). Unless the context makes clear otherwise,“combination therapy” may include the administration of dosage forms ofan Axl inhibitor combined with the dosage forms of one or more immunecheckpoint (activity) modulators. Unless the context makes clearotherwise, “combination therapy” may include different routes ofadministration for the Axl inhibitor and for the one or more immunecheckpoint (activity) modulators. Dosage forms, routes of administrationand pharmaceutical compositions include, but are not limited to, thosedescribed herein.

Axl inhibitors (particularly the compounds of formula (I), as definedabove) are small molecule inhibitors of Axl catalytic activity, and aretherefore useful in treating diseases and conditions which areassociated with Axl catalytic activity, which includes cancer andmetastatic cancer. In particular, diseases and conditions which arealleviated by the modulation of Axl activity include, but are notlimited to, solid cancer tumors, including, but not limited to, breast,renal, endometrial, bladder, ovarian, thyroid, and non-small cell lungcarcinoma, melanoma, prostate carcinoma, sarcoma, gastric cancer anduveal melanoma, and liquid tumors, including but not limited to,leukemias (particularly myeloid leukemias) and lymphomas.

In addition to the foregoing, Axl inhibitors are useful in treatingdiseases and conditions which are affected by the following biologicalprocesses: invasion, migration, metastasis, or drug resistance asmanifested in cancer, and stem cell biology as manifested in cancer.

Similarly, immune checkpoint (activity) modulators have been implicatedfor use in the same conditions.

When a cancer spreads (metastasises) from its original site (primarytumor) to another area of the body, it is termed “metastatic cancer”.Virtually all cancers have the potential to spread this way.

The treatment of metastatic cancer depends on where the primary tumor islocated. When breast cancer spreads to the lungs, for example, itremains a breast cancer and the treatment is determined by themetastatic cancer origin within the breast, not by the fact that it isnow in the lung. About 5 percent of the time, metastatic cancer isdiscovered but the primary tumor cannot be identified. The treatment ofthese metastatic cancers is dictated by their location rather than theirorigin. Metastatic cancers are named by the tissue of the original tumor(if known). For example, a breast cancer that has spread to the lung iscalled metastatic breast cancer to the lung.

Metastases spread in three ways: by local extension from the tumor tothe surrounding tissues, through the bloodstream to distant sites orthrough the lymphatic system to neighboring or distant lymph nodes. Eachkind of cancer may have a typical route of spread.

Tissues which are particularly susceptible to metastatic cancer are thebrain, liver, bone and lung, although all tissues of the body may beaffected. Any cancer may spread to the brain, although the most commonto do so are lung and breast cancer. The most common cancer tometastasize to the liver is colon or other gastrointestinal cancer. Themost common cancers to spread to the bones are prostate, lung and breastcancer. Metastases to the lung are common for many types of cancer.

The combination therapies of the invention are also useful in treatingcertain cellular proliferative disorders. Such disorders include, butare not limited to, the following:

a) proliferative disorders of the breast, which include, but are notlimited to, invasive ductal carcinoma, invasive lobular carcinoma,ductal carcinoma, lobular carcinoma in situ and metastatic breastcancer;

b) proliferative disorders of the skin, which include, but are notlimited to, basal cell carcinoma, squamous cell carcinoma, malignantmelanoma and Karposi's sarcoma;

c) proliferative disorders of the respiratory tract, which include, butare not limited to, small cell and non-small cell lung carcinoma,bronchial adema, pleuropulmonary blastoma and malignant mesothelioma;

d) proliferative disorders of the brain, which include, but are notlimited to, brain stem and hyptothalamic glioma, cerebellar and cerebralastrocytoma, medullablastoma, ependymal tumors, oligodendroglial,meningiomas and neuroectodermal and pineal tumors;

e) proliferative disorders of the male reproductive organs, whichinclude, but are not limited to, prostate cancer, testicular cancer andpenile cancer;

f) proliferative disorders of the female reproductive organs, whichinclude, but are not limited to, uterine cancer (endometrial), cervical,ovarian, vaginal, vulval cancers, uterine sarcoma and ovarian germ celltumor;

g) proliferative disorders of the digestive tract, which include, butare not limited to, anal, colon, colorectal, esophageal, gallbladder,stomach (gastric), pancreatic cancer, pancreatic cancer-Islet cell,rectal, small-intestine and salivary gland cancers;

h) proliferative disorders of the liver, which include, but are notlimited to, hepatocellular carcinoma, cholangiocarcinoma, mixedhepatocellular cholangiocarcinoma, primary liver cancer and metastaticliver cancer;

i) proliferative disorders of the eye, which include, but are notlimited to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma;

j) proliferative disorders of the head and neck, which include, but arenot limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngealcancers, and lip and oral cancer, squamous neck cancer, metastaticparanasal sinus cancer;

k) proliferative disorders of lymphocytic cells, which include, but arenot limited to, various T cell and B cell lymphomas, non-Hodgkinslymphoma, cutaneous T cell lymphoma, Hodgkins disease, and lymphoma ofthe central nervous system;

l) leukemias, which include, but are not limited to, acute myeloidleukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, and hairy cell leukemia,

m) proliferative disorders of the thyroid, which include, but are notlimited to, thyroid cancer, thymoma, malignant thymoma, medullarythyroid carcinomas, papillary thyroid carcinomas, multiple endocrineneoplasia type 2A (MEN2A), pheochromocytoma, parathyroid adenomas,multiple endocrine neoplasia type 2B (MEN2B), familial medullary thyroidcarcinoma (FMTC) and carcinoids;

n) proliferative disorders of the urinary tract, which include, but arenot limited to, bladder cancer;

o) sarcomas, which include, but are not limited to, sarcoma of the softtissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma;

p) proliferative disorders of the kidneys, which include, but are notlimited to, renal cell carcinoma, clear cell carcinoma of the kidney;and renal cell adenocarcinoma;

q) precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acutelymphoblastic leukemia), B-cell chronic lymphocytic leukemia/smalllymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma, splenic marginal zone B-cell lymphoma, hairy cell leukemia,plasma cell myeloma/plasmacytoma, extranodal marginal zone B-celllymphoma of MALT type, nodal marginal zone B-cell lymphoma, follicularlymphoma, mantle-cell lymphoma, diffuse large B-cell lymphoma,mediastinal large B-cell lymphoma, primary effusion lymphoma andBurkitt's lymphoma/Burkitt cell leukemia

(r) precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acutelymphoblastic leukemia), T-cell prolymphocytic leukemia, T-cell granularlymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosisfungoides/Sezary syndrome, anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, peripheral T-cell lymphoma, not otherwisecharacterized, angioimmunoblastic T-cell lymphoma, anaplastic large-celllymphoma, T/null cell, and primary systemic type;

(s) nodular lymphocyte-predominant Hodgkin's lymphoma, nodular sclerosisHodgkin's lymphoma (grades 1 and 2), lymphocyte-rich classical Hodgkin'slymphoma, mixed cellularity Hodgkin's lymphoma, and lymphocyte depletionHodgkin's lymphoma;

(t) myelogenous leukemia (e.g., Philadelphia chromosome positive(t(9;22)qq34;q11)), multiple myeloma, chronic neutrophilic leukemia,chronic eosinophilic leukemia/hypereosinophilic syndrome, chronicidiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia,juvenile myelomonocytic leukemia, refractory anemia with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, Sq-syndrome, andmyelodysplastic syndrome with t(9; 12)(q22;p12);

(u) AML with t(8;21)(q22;q22), AMLI(CBF-alpha)/ETO, acute promyelocyticleukemia (AML with t(15;17)(q22;q11-12) and variants, PML/RAR-alpha),AML with abnormal bone marrow eosinophils (inv(16)(p13q22) ort(16;16)(p13;ql1), CBFb/MYHI IX), and AML with llq23 (MLL)abnormalities, AML minimally differentiated, AML without maturation, AMLwith maturation, acute myelomonocytic leukemia, acute monocyticleukemia, acute erythroid leukemia, acute megakaryocytic leukemia, acutebasophilic leukemia, and acute panmyelosis with myelofibrosis.

In a preferred embodiment, the Axl inhibitor and the one or more immunecheckpoint (activity) modulators are useful in preventing, treatingand/or managing breast cancer, renal cancer, lung cancer, bladdercancer, prostate cancer, melanoma and/or lymphomas, and metastaticcancers (preferably breast cancer and metastatic breast cancer to thelung).

The antiproliferative effect of a combination therapy of the inventionmay be assessed by administering the active ingredients of thecombination therapy to a cultured tumor cell line. In the context of anin vitro assay, administration of an active ingredient may be simplyachieved by contacting the cells in culture with the active ingredientin amounts effective to inhibit cell proliferation. Alternatively, theantiproliferative effect of a combination therapy of the invention maybe assessed by administering the active ingredients of the combinationtherapy to an animal in an approved in vive model for cellproliferation.

Examples of tumor cell lines derived from human tumors and available foruse in the in vivo studies include, but are not limited to, leukemiacell lines (e.g., CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPM 1-8226, SR,P388 and P388/ADR); non-small cell lung cancer cell lines (e.g.,A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460,NCI-H522 and LXFL 529); small cell lung cancer cell lines (e.g., DMS 114and SHP-77); colon cancer cell lines (e.g., COLO 205, HCC-2998, HCT-116,HCT-15, HT29, KMI2, SW-620, DLD-1 and KM20L2); central nervous system(CNS) cancer cell lines (e.g., SF-268, SF-295, SF-539, SNB-19, SNB-75,U251, SNB-78 and XF 498); melanoma cell lines (e.g., LOX I MVI,MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62,RPMI-7951 and M19-MEL); ovarian cancer cell lines (e.g., IGROVI,OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8 and SK-OV-3); renal cancer cell lines(e.g., 786-0, A498, ACHN, CAKI-1, RXF 393, SNI2C, TK-10, UO-31, RXF-631and SNI2K1); prostate cancer cell lines (e.g., PC-3 and DU-145); breastcancer cell lines (e.g., MCF7, NCI/ADR-RES, MDA-MB-231/ATCC, HS 578T,MDA-MB-435, BT-549, T-47D and MDA-MB-468); and thyroid cancer cell lines(e.g., SK-N-SH).

The combination therapies of the invention can be tested for thetreatment of leukemias and lymphomas by testing the combination therapyin the xenograft in SCID mouse model using human Axl-expressing cancercell lines including, but not limited to, HeLa, MDA-MB-231, SK-OV-3,OVCAR-8, DU145, H1299, ACHN, A498 and Caki-1. In addition, thecombination therapy may be tested for its use in treating leukemias inthe xenograft in SCID or nu/nu mouse model using human Axl-expressingAML and CML leukemia cell lines.

The combination therapies of the invention may be tested for efficacy inpreventing, treating or managing metastatic cancers in known animalmodels of metastatic cancer, such as the Mouse 4T1 Breast Tumor Model(see Pulaski, B. A. et al., Current Protocols in Immunology (2000),20.2.1-20.2.16) or variations thereof.

Pharmaceutical compositions of Axl inhibitors and other agents are knownor can be prepared according to methods known to one skilled in the art.For example, methods of preparing and formulating pharmaceuticalcompositions of the Axl inhibitors of formula (I), as defined above, aredisclosed in PCT Published Patent Application No. 2008/083367, as wellas methods of administration.

In general, the amount of an Axl inhibitor or the amount of one or moreimmune checkpoint (activity) modulators which will be effective in thetreatment, prevention or management of cancer in the combinationtherapies of the invention can be determined by standard researchtechniques. For example, the dosage amount of each active ingredient ina combination therapy of the invention which will be effective in thetreatment, prevention or management of cancer can be determined byadministering the combination therapy to an animal model such as theones described herein or by one known to one skilled in the art. Inaddition, in vivo assays may optionally be employed to help identifyoptimal dosage ranges of each active ingredient in a combination therapyof the invention.

Selection of the preferred prophylactically or therapeutically effectivedose of an active ingredient used in the combination therapies of theinvention can be determined (e.g., by clinical trials) by a skilledartisan based upon the consideration of several factors, including theactivity of the specific compound employed; the metabolic stability andlength of action of the compound; the age, body weight, general health,sex, and diet of the patient; the mode and time of administration; therate of excretion; the drug combination; and the severity of themetastatic cancer.

The precise dose of either the Axl inhibitor or the immune checkpoint(activity) modulators used in the combination therapies of the inventionwill also depend on the route of administration and the seriousness ofthe cancer and should be decided according to the judgment of themedical practitioner and each patient's circumstances. Effective dosesmay be extrapolated from dose-response curves derived from in vitro oranimal model test systems.

For example, a therapeutically effective daily dose for an Axlinhibitor, i.e., a compound of formula (I), as defined above, is (for a70 kg mammal) from about 0.001 mg/kg (i.e., 0.07 mg) to about 100 mg/kg(i.e., 7.0 gm); preferably a therapeutically effective dose is (for a 70kg mammal) from about 0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e.,3.5 gm); more preferably a therapeutically effective dose is (for a 70kg mammal) from about 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e.,1.75 gm).

Dosages, routes of administration and recommended usage of the immunecheckpoint (activity) modulators used in the combination therapies ofthe invention are known in the art and often described in suchliterature as the Physician's Desk Reference (current edition). Inaddition, typical doses of immune checkpoint (activity) modulators maybe the same as the Axl inhibitor as described above.

In the combination therapies of the invention, an Axl inhibitor isadministered simultaneously with, prior to, or after administration ofone or more immune checkpoint (activity) modulators, as describedherein, by the same route of administration or by different routes. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains an Axl inhibitor and one or moreadditional immune checkpoint (activity) modulators, as well asadministration of the Axl inhibitor and each immune checkpoint inhibitorin its own separate pharmaceutical dosage formulation. For example, theAxl inhibitor and the other one or more immune checkpoint (activity)modulators can be administered to the patient together in a single oraldosage composition such as a tablet or capsule, or each agent can beadministered in separate oral dosage formulations. Where separate dosageformulations are used, the Axl inhibitor and the one or more immunecheckpoint (activity) modulators can be administered to the patient atessentially the same time, i.e., concurrently, or at separatelystaggered times, i.e., sequentially. All such combinations ofadministration are encompassed by the combination therapies of theinvention.

In certain embodiments of the combination therapies of the invention,the Axl inhibitor is administered to a patient, preferably a human,concurrently with one or more immune checkpoint (activity) modulatorsuseful for the treatment of cancer. The term “concurrently” is notlimited to the administration of the active ingredients (i.e., the Axlinhibitor and the one or more immune checkpoint (activity) modulators)at exactly the same time, but rather it is meant that the Axl inhibitorand the immune checkpoint (activity) modulators are administered to apatient in a sequence and within a time interval such that the Axlinhibitor can act together with the immune checkpoint (activity)modulators to provide an increased benefit than if they wereadministered otherwise. For example, each active ingredient of thecombination therapies of the invention may be administered at the sametime or sequentially in any order at different points in time; however,if not administered at the same time, they should be administeredsufficiently close in time so as to provide the desired therapeutic orprophylactic effect. Each active ingredient can be administeredseparately, in any appropriate form and by any suitable route. Invarious embodiments, the active ingredients are administered less than 1hour apart, at about 1 hour apart, at about 1 hour to about 2 hoursapart, at about 2 hours to about 3 hours apart, at about 3 hours toabout 4 hours apart, at about 4 hours to about 5 hours apart, at about 5hours to about 6 hours apart, at about 6 hours to about 7 hours apart,at about 7 hours to about 8 hours apart, at about 8 hours to about 9hours apart, at about 9 hours to about 10 hours apart, at about 10 hoursto about 1 hours apart, at about 11 hours to about 12 hours apart, nomore than 24 hours apart or no more than 48 hours apart. In preferredembodiments, two or more active ingredients are administered within thesame patient visit.

In other embodiments, the active ingredients are administered at about 2to 4 days apart, at about 4 to 6 days apart, at about 1 week part, atabout 1 to 2 weeks apart, or more than 2 weeks apart. In preferredembodiments, the active ingredients are administered in a time framewhere both active ingredients are still prophylactically andtherapeutically active. One skilled in the art would be able todetermine such a time frame by determining the half life of theadministered active ingredients.

In certain embodiments, the active ingredients of the invention arecyclically administered to a patient. Cycling therapy involves theadministration of a first active ingredient, such as the Axl inhibitor,for a period of time, followed by the administration of the secondand/or third active ingredient for a period of time and repeating thissequential administration. Cycling therapy can reduce the development ofresistance to one or more of the therapies, avoid or reduce the sideeffects of one of the therapies, and/or improves the efficacy of thetreatment.

In certain embodiments, the active ingredients are administered in acycle of less than about 3 weeks, about once every two weeks, about onceevery 10 days or about once every week. One cycle can comprise theadministration of an active ingredient by infusion over about 90 minutesevery cycle, about 1 hour every cycle, about 45 minutes every cycle.Each cycle can comprise at least 1 week of rest, at least 2 weeks ofrest, at least 3 weeks of rest. The number of cycles administered isfrom about 1 to about 12 cycles, more typically from about 2 to about 10cycles, and more typically from about 2 to about 8 cycles.

In yet other embodiments, the active ingredients of the combinationtherapies of the invention are administered in metronomic dosingregimens, either by continuous infasion or frequent administrationwithout extended rest periods. Such metronomic administration caninvolve dosing at constant intervals without rest periods.

In other embodiments, the active ingredients are administeredconcurrently to a patient such that doses of the immune checkpoint(activity) modulators are administered separately yet within a timeinterval such that the Axl inhibitor can work together with the immunecheckpoint (actively) modulators. For example, the immune checkpoint(activity) modulator may be administered one time per week and the Axlinhibitor may be administered every day. In other words, the dosingregimens for the active ingredients are carried out concurrently even ifthe active ingredients are not administered simultaneously or within thesame patient visit.

FIGURES

FIG. 1 shows the post-immune response tumour recurrence and metastasisin the mammary adenocarcinoma 4T1-Luc/Balb/C syngeneic mouse model. Thetop image shows control shRNA and the bottom image shows shAXL. Detectedimages are shown in the adjacent Table.

FIGS. 2A-B show body weight changes (BWC) in Balb/e mice carrying 4T1orthotopic tumors treated with vehicle, 50 mg/kg BGD324 Did or 10 mg/kgCTLA-4/PD-1 (each) in combinations or alone as indicated over the courseof 46 (a) or (b) 104 days. Means±SEM are plotted, n=4 (vehicle), 5(BGB324), 9 (CTLA4/PD1+/−BGB324 and CTLA4-BGB324). The sudden drop inBWC in Group D at day 38 is due to euthanisation of mice.

FIGS. 3A-C show transformed survival curves of Balb/e mice carrying 4Torthotopic tumors treated with vehicle, BGB324 or CTLA-4/PD-1 alone orin combinations as indicated for 46 (a) or 104 (b and c) days. Endpointsfor survival were set to the day when the tumor reached 500 mm³.Significance by Mantel-Cox; *p<0.05; *p<0.01; ***p<0.001; ****p<0.0001;ns: not significant.

FIG. 4 shows tumor volumes at day 28 after treatment initiation of alltumors presented in FIGS. 3 (a-c).

FIG. 5 shows the combined transformed survival curves for two separatemouse experiments of Balb/c mice carrying 4T1 orthotopic tumors treatedwith vehicle, CTLA-4/PD-1 or CTLA-4/PD-1+BGB324. The studies combined inthe survival curves are presented in FIG. 2 (Report153-SR-502P1MS6.2_Ver2) and in Report 102-SR-324; data not presentedindividually here). Significance by Mantel-Cox.

FIG. 6 shows enhanced tumor infiltration of anti-tumorigenic Cytotoxic Tcells (CTLs) in Balb/c mice carrying 4T1 orthotopic tumors treated withCTLA-4/PD-1+BGB324 compared to CTLA-4/PD1-alone. Tumors were analysed atday 11 after treatment initiation as described in legends to FIG. 1 .

FIG. 7 shows enhanced presence of anti-tumorigenic Natural Killer cells,macrophages and Neutrophiles in spleens of Balb/c mice carrying 4T1orthotopic tumors treated with CTLA-4/PD-1-1BGB324 compared toCTLA-4/PD-1 alone. Tumors were analysed at day 11 after treatmentinitiation as described in legends to FIG. 1 . Significance by one-wayANOVA.

FIG. 8 shows reduced presence of pro-tumorgenic Myelo Derived SuppressorCells (mMDSCs) in spleens of Balb/c mice carrying 4T1 orthotopic tumorstreated with CTLA-4/PD-1+BGB324 compared to CTLA-4/PD-1 alone. Tumorswere analysed at day 11 after treatment initiation as described inlegends to FIG. 1 .

FIG. 9 shows body weight changes (BWC) C57Bl/6 mice carryingsubcutaneous Lewis Lung tumors treated with vehicle, 50 mg/kg BGB324 Bidor 10 mg/kg BGB324 or 10 mg/kg PD-1/PD-L1 (each) alone or incombinations as indicated over the course of 21 days. Means±SEM areplotted, n=10 for all groups.

FIG. 10 shows transformed survival curves of C57Bl/6 mice carryingsubcutaneous Lewis Lung tumors treated with vehicle, BGB324 Bid orPD-1/PD-L alone or in combinations as indicated. Endpoints for survivalwere set to the day when the tumor reached 500 mm³. Significance byMantel-Cox test.

FIG. 11 shows average tumor volumes for C57Bl/6 mice carryingsubcutaneous Lewis Lung tumors treated with vehicle, BGB324 orPD-1/PD-L1 alone or in combinations as indicated. Means±SEM are plotted,n=10 for all groups. Significance by Two-way ANOVA; p<0.0001.

FIG. 12 shows tumor volumes at day 21 after treatment initiation for allmice presented in FIG. 11 . Significance by Mann Whitney test; **p<0.01.

FIG. 13 shows enhanced tumor infiltration of anti-tumorigenic CytotoxicT cells (CTLs) and Natural Killer cells (NK) in C57Bl/6 mice carryingsubcutaneous Lewis Lung tumors treated with PD-1/PD-L1+BGB324 comparedto PD-1/PD-L1 alone Tumors were analysed at day 21 after treatmentinitiation as described in legends to FIG. 9 . Significance by one-wayANOVA. **p<0.01; ***p<0.01

FIG. 14 shows reduced presence of pro-tumorgenic Myelo DerivedSuppressor Cells (mMDSCs) in C57Bl/6 mice carrying subcutaneous LewisLung tumors treated with PD-1/PD-L1+BGB324 compared to PD-1/PD-L1 alone.Tumors were analysed at day 21 after treatment initiation as describedin legends to FIG. 9 .

FIG. 15 shows a typical survival curve for mice treated with oncolyticvirus, oncolytic virus/immune checkpoint (activity) modulator, andoncolytic virus/immune checkpoint (activity) modulator/anti-Axl.

EXAMPLES

Compounds of formula (I) utilised in the combination therapies of theinvention can be made using organic synthesis techniques known to thoseskilled in the art, as well as by the methods described in PCT PublishedPatent Application No. WO 2008/083367. Specific examples of thecompounds of formula (I) can be found in this publication.

Alternatively, certain compounds of formula (I), as defined above, canbe made by the methods disclosed in PCT Published Patent Application No.WO 2010/083465.

Biological Examples

The following biological examples are provided by way of illustration,not limitation. In the following biological examples,1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,which is a compound of formula (I), as defined above, and which isdesignated in the following examples and the Figures as “BGB324”,“Compound A” or “Cpd A” or “Cmpd A”, was assayed for its ability toprevent, treat or manage cancer in combination with immune checkpoint(activity) modulators.

ABBREVIATIONS

TKI Tyrosine Kinase Inhibitor

CTLA-4 Cytotoxic T-Lymphocyte Antigen 4

PD-1 Programmed Death Receptor-1

Qd Once a day

PO Per Orally

FBS Fetal Bovine Serum

SOP Standard Operating Procedures

SC Subcutaneous

Experimental Procedures

Materials

Experimental Animals for Syngeneic 4T1 and 4T1-Luc Model:

-   -   Species/Strain: Balb/c ABomTac    -   Source: Taconic Farms    -   Sex: Female    -   Weight: 20-30 grams on the day of implantation    -   Age: at least 6 weeks old on the day of randomization    -   Animal Identification: Cage number and ear notching        Experimental Animals for Syngeneic Lewis Lung Model:    -   Species/Strain: C57BL/6JOlaHsd    -   Source: Harlan Laboratories    -   Sex: Female    -   Weight: 20-30 grams on the day of implantation    -   Age: at least 6 weeks old on the day of randomization    -   Animal Identification: Cage number and ear notching        Cells and Materials:    -   RPMI-1640 (Sigma, Cat. # R8758) supplemented with 10% fetal        bovine serum (FBS), L-glutamine (4 mM), streptomycin (5 μg/ml)        and penicillin (5 U/ml).    -   BD Matrigel™ Basement Membrane Matrix Growth Factor Reduced, BD        Bioscience, Cat. #354230, Lot #2229975.    -   0.25% Trypsin-EDTA, Sigma, Cat. # SLBD8049.        Drugs        Vehicle: 0.5% HPMC/0.1% Tween 80 vehicle for BGB324. Sterile PBS        for immune checkpoint inhibitors.        IgG: InVivoMAb Polyclonal Armenian Hamster IgG, BE0091,        BioXCell, Isotype control for IP injections.        BGB324: Manufacturer: Almac Group, N Ireland, batch Q1080.        BGB324 powder was stored at room temperature. The BGB324 dosage        given was well below the MTD in mice (023-TR-324). The BGB324        dosage administered (50 mg/kg Bid) is expected to result in a        plasma concentration in mice (micro molar range) that is        comparable to the one achieved in humans after administration of        BGB324 (micromolar range). BGB324 was diluted in vehicle to 5        mg/ml dosing solution and administered to the mice immediately.        BGB324 solution was freshly prepared every day.        Anti-mCTLA-4 (CD152) monoclonal antibody (CTAA-4): Syrian        Hamster IgG, clone 9H10 (BioXCell, Cat. # BE0131).        Anti-mPD-1 monoclonal antibody (PD-1): rat IgG2a, clone RMP1-14        (BioXCell, Cat. # BE0146).        Anti-mPD-L1 monoclonal antibody (PD-L1): rat IgG2b, clone        10F.9G2 (BioXCell, Cat # BE0101).        Methods        Cell Culture        4T1 mammary adenocarcinoma cells and Non Small Cell Lung Cancer        (NSCLC) Lewis Lung (LL2) were propagated at sub-confluence and        split on a regular basis every 3^(rd) day.        After trypsinization, the cells were washed once in RPMI/FBS (7        min at 1200 rpm) and re-suspended at 4×10⁶ cells/ml (4T1 cells)        or 2.5×10⁶ per ml (LL2 cells) in a mixture of serum-free RPMI        medium and Matrigel (1:1).        Subcutaneous Tumor Inoculation        Each animal was weighed before cell implantation. Injection of        cells was performed after anesthetizing of mice by inhalation of        sevoflurane. Anesthesia was induced with 8% sevoflurane and        maintained at 4%. During injection, the mouse was placed on a        heating pad. For implantation of 4T1 tumors: under a suitable        depth of unconsciousness, each mouse was shaved and skin        surrounding the region was washed with Chlorhexidine (1 mg/ml)        with use of sterile gauze. Cells were injected into the 4^(th)        mammary gland on the right side with 0.05 ml cell suspension        comprising approximately 2×10⁵ 4T1 cells in serum-free RPMI        medium/Matrigel (1:1). The mice were kept under surveillance        until regaining of consciousness. For implantation of LL2        tumors: under a suitable depth of unconsciousness, animals were        shaved, and skin surrounding the region was washed with        Chlorhexidine (1 mg/ml) with use of sterile gauze. Injection was        subcutaneous with one tumor per mouse with 0.1 ml of        approximately 2.5×10⁵ LLC cells in serum-free RPMI        medium/Matrigel (1:1).        Assignment of Experimental Groups        Before commencement of treatment, the animals were weighted and        the tumor volume was measured twice a week. Since the tumor        volume can affect the effectiveness of any given treatment, the        mice were randomized into the groups using a Latin square        method. Randomization was based on the tumor volume to ensure        that each animal had the same probability of being assigned to a        given treatment to reduce systematic error and that treatment        groups were comparable at the baseline. When the average tumor        volume reached 50-100 mm³, animals were randomized into        treatment groups.        Dosing Procedure        Dosing administration was 10 ml/kg PO (BGB324 and 0.5% HPMC/0.1%        Tween 80) and the dosing schedule was twice a day (Bid) on a 5        days on, 2 days off schedule. Dosing administration was 10 ml/kg        IP (IgG, anti-mPD-1, anti-mPD-L1 and anti-mCTLA-4) by a 30-gauge        needle. For the 4T1 model, dosing schedule was 4 times with        CTLA4 and PD1 on days 0, 2, 4 and 6. For the Lewis Lung model,        dosing schedule was 4 times with PD1 and PD-L1 on days 4, 8, 14        and 18 on days 0, 2, 4 and 6, respectively.        Clinical Observations        Animals were weighed prior to dosing, together with tumor growth        measurements, and prior to euthanasia. At the time of routine        monitoring, animals were checked for any effects of tumor growth        or treatments on normal behavior, such as mobility, dehydration,        body weight gain/loss, eye matting and any other abnormal        effect. Death and observed clinical signs were recorded.        Non-fasted body weights were recorded every day.        Tumor Measurements and Endpoint        Tumor measurements: Tumor size was measure twice a week in two        dimensions using a caliper, and the tumor volume was calculated        using the formula: V=0.5 a×b²[mm³], where a and b are the long        and short diameter of the tumor, respectively (see Attachment 6        for raw data).        Endpoint: Mice were euthanized with CO₂. Tumors and spleens were        snap frozen in liquid nitrogen and stored in a −80° C. freezer,        and/or fixed in 4% formaldehyde, transferred to 70% ethanol        after 24 h and stored at 4° C. and/or subjected to tissue        dissociation for analysis of immune cell infiltration. Liver and        lungs were fixed in 4% formaldehyde, transferred to 70% ethanol        after 24 h and stored at 4° C. for further evaluation.        Statistical Analysis        The tumor volume of 500 mm³ was used as an endpoint for the        survival analysis. The Kaplan-Meier survival plots were        generated using the software program PRISM (GraphPad) and the        survival curves were compared using a log-rank (Mantel-Cox)        test. Figures were generated using software PRISM (GraphPad).        For individual time points, tumor volume values of different        treatment groups were compared with other groups and        significance was determined by one-way ANOVA or two-tailed        unpaired t-test using software PRISM (GraphPad). Differences        between the groups were considered significant when P<0.05.        Figures were generated using software PRISM (GraphPad).        Results        AXL is Necessary for Evation of Anti-Tumorgenic Immune Response        An initial robust anti-tumor immune response to the 4T1^(Luc)        cell luciferase/GFP neo-antigens resulted in complete tumor        regression (FIG. 1 ). After 4 weeks, tumor immune escape with        robust regrowth of the primary tumor and multiorgan metastasis        was detectable in all control animals. In contrast, AXL        knockdown completely blocked post-immune response tumor regrowth        and metastasis. This indicates that AXL is required for tumor        immune escape in this model.        BGB324 Potentiates the Effect of Immune Checkpoint Inhibiting        Therapy and Enhances the Presence of Pro-Tumorgenic CTLs and NK        Cells in Syngeneic Mouse Models of Breast and Lung Cancer.        Body Weight Changes        Body weight changes in 4T1 implanted Balb/c mice as a result of        treatment with vehicle, BGB324 or CTLA-4/PD-1 alone or in        combination over the course of 104 days were recorded; the        results are shown in FIG. 2 . In general, a drop in body        weight >20% would indicate treatment toxicity and should lead to        termination of the treatment and culling of the mouse. None of        the treatment groups showed a reduction in body weight that        could indicate treatment toxicity.        Body weight changes in Lewis Lung implanted C57Bl/6 mice as a        result of treatment with vehicle, BGB324 or PD-1/PD-L1 alone or        in combinations over the course of 21 days were recorded; the        results are shown in FIG. 9 . In the triple combination group        treated with PD-1/PD-L1+BGB324 a drop in body weight was        observed at day 21. For 2 mice this was so severe that the study        was terminated and tissue collected for analysis.        Effects of BGB324 on Survival and Tumor Volume Changes        For 4T1 tumor bearing Balb/C mice, durable tumor clearance was        observed in 23% of BGB324+CTLA-4/PD-L1 versus 5.6% CTLA4/PD1.        Complete tumor clearance was observed in 22% of BGB324+CTLA4        treated mice versus zero for CTLA4 (FIGS. 3-5 ). Following        treatment with BGB324+CTLA4/PD1 or BGB324+CTLA4, metastases were        abrogated in responders (Tables 1 and 2).

TABLE 1 Number of metastasis detected in lung, liver and spleen in micetreated with CTLA-4 or CTLA-4 + BGB324. CTLA-4 CTLA-4 + BGB324 LungLiver Spleen Lung Liver Spleen Non- 6/8 5/8 5/8 6/7 5/7 4/7 responders P= P = P = 0.02 0.09 0.19 Responders na na na 0/2 0/2 0/2

TABLE 2 Number of metastasis detected in lung, liver and spleen in micetreated with CTL-A4/PD-1 or CTLA-4/PD-1 + BGB324 CTLA-4/PD-1CTLA-4/PD-1 + BGB324 Lung Liver Spleen Lung Liver Spleen Non- 11/1510/15 12/15 14/16  9/16 10/16 responders P = P = P = 0.0009 0.006 0.102Responders 0/1 0/1 0/1 3/8 0/8 1/8Tables 1 and 2 show metastasis detected in Balb/c mice carrying 4T1orthotopic tumors treated with vehicle, BGB324 or CTLA-4/PD-1 alone orin combinations as indicated for the transformed survival studypresented in FIG. 3 c (Table 1) and FIG. 5 (Table 2). Significance byunpaired two-tailed Student t-test.For Lewis Lung tumor bearing C57BI/6 mice, BGB324 significantlyprolonged survival and reduced tumor burden when combined withPD-1/PD-L1 compared to PD-1/PD-L1 alone (FIGS. 10-12 ). Metastasis wasnot observed for any treatment groups in this model (data not shown).Effect of BGB324 on Immune Cell Sub-PopulationsBGB324 in combination with immune checkpoint inhibitors enhanced CTLtumor infiltration in both the 4T1 and Lewis Lung model (FIGS. 6 and 13respectively). In the Lewis lung model, also enhanced presence of NKcells (FIG. 13 ) was observed. For the 4T1 model, enhanced presence ofNK cells, macrophages and PMN neuotrophiles were found in the spleen(FIG. 7 ). In addition, a reduction in the presence of pro-tumorigenicmMDSC were observed in both models (FIGS. 8 and 14 ). These findingssupport that BGB324 can mediate its anti-tumorgenic effect (FIGS. 3, 4,5 and Tables 1 and 2; FIGS. 10-12 ) by enhancing the presence of tumorkilling immune cells such as CTLs and NK cells and by reducing thepresence of pro-tumorigenic neutrophils such as mMDSC.

CONCLUSION

Targeting AXL signaling represents a unique opportunity to addressmultiple tumor immune suppression mechanisms. Our results in breast andlung cancer mouse models support combining the clinical-stage AXLinhibitor, BGB324, with cancer immune checkpoint inhibitors to improvetreatment of human cancers.

REFERENCES

-   Chen L, 2014. Rejection of metastatic 4T1 breast cancer by    attenuation of Treg cells in combination with immune stimulation.    Mol Ther. 2007 December; 15(12):2194-202. Epub 2007 Oct. 30. PubMed    PMID: 17968355.-   Chen L, et al. 2014. Metastasis is regulated via microRNA-200/ZEB1    axis control of tumour cell PD-L1 expression and intratumoral    immunosuppression. Nat Commun. 2014 Oct. 28; 5:5241. doi:    10.1038/ncomms6241.-   Gjerdrum C, et al. 2010. Axl is an essential    epithelial-to-mesenchymal transition-induced regulator of breast    cancer metastasis and patient survival. Proc Natl Acad Sci USA. 2010    Jan. 19;107(3):1124-9. doi: 10.1073/pnas.0909333107. Epub 2009 Dec.    28.-   Grosso J F, et al. 2013. CTLA-4 blockade in tumor models: an    overview of preclinical and translational research. Cancer Immun.    2013; 13:5. Epub 2013 Jan. 22. Review. PubMed PMID: 23390376.-   Kyi C, et al. 2014. Checkpoint blocking antibodies in cancer    immunotherapy. FEBS Lett. 2014 Jan. 21; 588(2):368-76. doi:    10.1016/j.febslet.2013.10.015. Epub 2013 Oct. 23. Review.-   Lou Y, et al 2014. Association of epithelial-mesenchymal transition    status with PD1/PDL1 expression and a distinct immunophenotype in    non-small cell lung cancer: Implications for immunotherapy    biomarkers. J Clin Oncol 32:5s, 2014 (suppl; abstr 3018).-   Lu J, et al. 2014. Clinical evaluation of compounds targeting    PD-1/PD-L1 pathway for cancer immunotherapy. J Oncol Pharm Pract.    Epub ahead of print] PubMed PMID: 24917416.-   Paolino M, et al. 2014. The E3 ligase Cbl-b and TAM receptors    regulate cancer metastasis via natural killer cells. Nature. 2014    Mar. 27; 507(7493):508-12. doi: 10.1038/nature12998.-   Rothlin C V, et al. 2007. TAM receptors are pleiotropic inhibitors    of the innate immune response. Cell. 2007 Dec. 14; 131(6):1124-36.    Effect of Axl Inhibitor on Immune Checkpoint Inhibitor Efficacy    Background    Signaling via the Axl receptor tyrosine kinase is a key suppressor    of anti-tumour innate immune response. Axl is expressed on several    cells associated with the suppressive tumpour immune    microenvironment including natural killer cells, dendritic cells and    tumour-associated macrophages. Axl is also an important regulator of    tumour plasticity related to epithelial-to-mesenchymal transition    (EMT) that contributes to anti-tumour evasion. Hence Axl signaling    contributes uniquely to tumour intrinsic and microenvironmental    immune suppression in tumours. It was therefore evaluated whether    blocking Axl signaling with BGB324, a selective clinical-stage small    molecule checkpoint blockade in sygeneic cancer mouse models that    display limited immunogenicity.    Axl, EMT and Immune Suppression    Axl is a down-regulator of the innate immune response upon    activation of the adaptive immune system. Axl mediates M1 to Mr    polarisation (Chiu, K. C., et al. (2015). Oral Oncol). High Axl    expression on tumour associated macrophages in human primary breast    cancer (Ye, X., et al. (2010). Oncogene). TAM inhibition in NK cells    reduces metastasis from melanoma and mammary carcinoma (Paolino, M.,    et al. (2014). Nature). The Axl ligand Gas6 is upregulated by tumour    infiltrating macrophages and contributes to tumour growth and    metastasis (Loges, S., et al. (2010). Blood). High EMT score    correlates with immunosuppressive phenotype (Lou, Y., et al. (2014).    J Clin Oncol suppl; abstr 3018). PD-L1 expression correlates with    mesenchymal phenptype (Chen, L., et al. (2014). Nat Commun). The EMT    transcription factor Snail induces immunosuppression leading to    increased metastasis and confers resistance yo cytotoxic T cell    attack (Kudo-Saito, C., et al. (2009). Cancer Cell). EMT increases    autophagy flux, and autophagy inhibition sensitises EMTed cells to    cytotoxic T cell lysis (Akalay, I., et al. (2013) Cancer Res).    Axl Inhibition in Post-Immune Response Tumour Recurrence and    Metastasis in the Mammary Adenocarcinoma 4T1/Balb/C Syngeneic Mouse    Model    BalbC mice were orthotopically implanted with 1×106 4T1-GFPLuc cells    infected with the mouse Axl-targeting shRNA (4T1-GFPLuc-shmAxl2;    shAXL) or negative control human-specific shRNA    (4T1-GFP-Luc-shAxl279; control shRNA) cells. Tumour growth and    metastasis spread was monitored every week by bioluminescent    imaging. After 9 weeks, organs were excised and imaged ex vivo for    occurrence of metastasis. The results are shown in FIG. 1 . An    initial robust immune response induced tumours regression followed    by tumour immune evasion with regrowth of the primary tumour and    widespread metastasis in mice implanted with 4T1-GFP-Luc control    shRNA cells. Axl knock down suppressed regrowth at the primary site    and abolished metastasis (Gjerdrum, C., et al. (2010). Proc Natl    Acad Sci USA). This indicates that Axl contributes to immune    evasion.    Axl Inhibition Potentiates the Effect of Immune Checkpoint    Inhibitors in the Mammary Adenocarcinoma 4T1/Balb/C Syngeneic Mouse    Model    BalbC mice were orthotopically implanted with 4×105 4T1 cells.    Treatment was initiated when average tumour volume reached 100 mm³.    Animals were treated with anti-CTLA4 and anti-PD1 as indicated at 10    mg/kg of each (4 doses every 2nd day, IP). BGB324 was administered    at 50 mg/kg twice a day (oral gavage). Vehicle groups were injected    with control IgG. Transformed survival curves are shown. The day    each individual tumour reached 500 mm³ was used as an endpoint.    Complete tumour clearance was observed in 23% of the    anti-CTLA4/anti-PD1+BGB324 treated mice versus 5.6% for the    anti-CTLA4/anti-PD1 treated mice. Complete tumour clearance was    observed in 22% of the anti-CTLA4+BGB324 treated mice versus zero    for the anti-CTLA4 treated mice. BalbC mice that displayed complete    clearance of the tumour were re-injected orthotopically with 4T1    cells at day 105 after the first cell injection. Subsequent tumour    growth was not observed in any of these mice (from anti-CTLA4/PD-1    group, n=1; from anti-CTLA4/PD-1+BGB324, n=4) indicating that these    mice were immune towards subsequent 4T1 cell exposure. The results    are shown in FIG. 5 .    Axl Inhibition Treatment Enhances the Number of CTLs in Tumours and    Spleens    For CTL (cytotoxic T-lymphocyte) analysis in tumors: BalbC mice were    orthotopically implanted with 4×105 4T1 cells. Treatment    (anti-CTLA4+anti-PD1 at 10 mg/kg of each, 3 doses every 2nd day, IP;    BGB324 at 50 mg/kg twice a day, oral gavage; Vehicle control IgG at    20 mg/kg, 3 doses every 2nd day, IP) was initiated when average    tumour volume reached 500 mm³. Tumours were harvested 5 days after    treatment initiation (n=5 for all groups), dissociated using MACS    Tumor Dissociation Kit, stained for markers of CTLs and analysed on    a BD Fortessa Cell Analyser. Anti-CTLA4/PD1 treatment enhanced    infiltration of CTLs in 4T1 tumors when compared to Vehicle or    BGB324 treated mice. Treatment with BGB324 further enhanced tumour    infiltration of CTLs. The results are shown in FIG. 6 .    For CTL analysis in spleen: BalbC mice were orthotopically implanted    with 4×105 4T1 cells. Treatment (anti-CTLA4+anti-PD at 10 mg/kg of    each, 4 doses every 2nd day, IP; BGB324 as above) was initiated when    average tumor volume reached 100 mm³. Mice were culled 43 days after    treatment initiation. Spleens were dissociated using MACS Tumor    Dissociation Kit and stained for markers of CTLs. Responders (top    two points in CTLA4; top two points in CTLA4/PD1; top three points    in CTLA4/PD1/BGB324) in all groups had a higher number of CTLs in    the spleen compared to nonresponders (remaining points). BGB324    further enhanced the number of CTLs compared to treatment with    immune check point inhibitors alone.    Tumours Escaping Checkpoint Blockade Show an Increased Mesenchymal    Phenotype    BalbC were orthotopically implanted with 4×105 4T1 cells, and    treatment was initiated when average tumour volume reached 100 mm³.    Animals were treated with anti-CTLA4+anti-PD1 as indicated at 10    mg/kg of each (4 doses every 2nd day, IP). BGB324 was administered    at 50 mg/kg twice a day (oral gavage). Control groups were injected    with control IgG. Tumours were harvested from non-responders (i.e.    tumours that had escaped treatment inhibition and reached 1500 mm³)    and responders (i.e. tumours that responded to treatment and    remained below 500 mm³ until termination of experiment) and    processed by IHC for evaluation of known EMT markers.    Tumours treated with checkpoint inhibitors alone or in combination    with BGB324 that did not respond to the treatment, displayed    stronger staining for Axl and Vimentin compared tumours from the    control groups (vehicle, BGB324 alone). However, in a responding    tumour treated with BGB324+anti-CTLA4/anti-PD-1 weaker Axl- and    Vimentin staining were observed.    This suggests that EMT is involved in the immune evasion of tumors    escaping checkpoint inhibition, and that targeting Axl may inhibit    EMT mediated immune evasion.

CONCLUSION

This data therefore shows that Axl inhibition (particularly by BGB324)represents an unique opportunity to target anti-tumour immunesuppressive mechanisms and supports clinical translation of Axlinhibition in combination with cancer immunotherapy in human cancers.Effect of Anti-Axl, Oncolytic Virus and Immune Checkpoint InhibitorCombination Therapy on MetastasisTumours are implanted into female Balb/c mice and mice are injected whentumours reach ˜50-100 mm³. Tumour volume is monitored by calipermeasurement and defined by V(mm³)=π/6×W2×L, where W and L are the widthand the length of the tumour, respectively. Mice are injected with 2×10⁸plaque forming units (pfu) of Oncolytic Virus (OV) through the tail veinstarting at day 0. For the anti-Immune Checkpoint Inhibitor (ICI) group,100 μg of anti-ICI antibody is injected intraperitoneally (IP) at day 4after virus injection, with treatments consisting of 3 doses each 3 daysapart. For the combination group, anti-Axl is administered along withthe OV at day 0, then 100 μg of anti-ICI antibody is administered at day4. Anti-Axl treatment is either monoclonal anti-Axl antibody or a smallmolecule Axl inhibitor. The anti-Axl antibody is administered IP atdoses of 30 mg/kg body weight, twice weekly. The small moleculeinhibitor is administered at 50 mg/kg in 0.5% (w/w) HPMC/0.1% (w/w)Tween 80 twice daily by oral gavage. For the Kaplan-Meier survivalcurve, end point is established at a tumour volume ≥750 mm³. A typicalresult is shown in FIG. 15 .

The invention claimed is:
 1. A method of controlling cancer in a patientcomprising administering to the patient in need thereof atherapeutically effective amount of an Axl inhibitor in concurrent,separate or sequential combination with a therapeutically effectiveamount of at least two immune checkpoint inhibitors wherein the Axlinhibitor is a compound of formula (I):

wherein: R¹, R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R⁸,—C(O)N(R⁶)R⁷, and —C(═NR⁶)N(R⁶)R⁷; R² and R³ are each independently apolycyclic heteroaryl containing more than 14 ring atoms optionallysubstituted by one or more substituents selected from the groupconsisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,—R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where pis 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,—R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,—R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶) S(O)_(t)R⁸ (where t is 1 or2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); or R² is apolycyclic heteroaryl containing more than 14 ring atoms as describedabove and R³ is selected from the group consisting of aryl andheteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); orR³ is a polycyclic heteroaryl containing more than 14 ring atoms asdescribed above, and R² is selected from the group consisting of aryland heteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2);each R⁶ and R⁷ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,—R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷, together with thecommon nitrogen to which they are both attached, form an optionallysubstituted N-heteroaryl or an optionally substituted N-heterocyclyl;each R⁸ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkynyl; each R⁹ is independently selected from the groupconsisting of a direct bond, an optionally substituted straight orbranched alkylene chain, an optionally substituted straight or branchedalkenylene chain and an optionally substituted straight or branchedalkynylene chain; each R¹⁰ is independently selected from the groupconsisting of an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chainand an optionally substituted straight or branched alkynylene chain;each R¹¹ is independently selected from the group consisting ofhydrogen, alkyl, cyano, nitro and —OR⁸; each R¹² is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl,haloalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,—R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R^(12's), together with thecommon nitrogen to which they are both attached, form an optionallysubstituted N-heterocyclyl or an optionally substituted N-heteroaryl;each R¹³ is independently selected from the group consisting of a directbond, an optionally substituted straight or branched alkylene chain andan optionally substituted straight or branched alkenylene chain; andeach R¹⁴ is independently selected from the group consisting of anoptionally substituted straight or branched alkylene chain and anoptionally substituted straight or branched alkenylene chain; as anisolated stereoisomer or mixture thereof or as a tautomer or mixturethereof, or a pharmaceutically acceptable salt or N-oxide thereof, andwherein one of the at least two immune checkpoint inhibitors is ananti-CTLA-4 antibody or an anti-PD-1 antibody; and wherein the cancer isan Axl-expressing cancer.
 2. The method according to claim 1, whereinthe compound of formula (I) is selected from the group consisting of:1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;and1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,or pharmaceutically acceptable salts thereof.
 3. The method according toclaim 1, wherein the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,or a pharmaceutically acceptable salt thereof.
 4. The method accordingto claim 1, wherein the at least two immune checkpoint inhibitors areselected from the group consisting of anti-CTLA-4 antibodies, anti-PD-1antibodies, anti-PD-L1 antibodies, anti-4-1BB antibodies, anti-OX-40antibodies, anti-GITR antibodies, anti-CD27 antibodies, anti-CD40antibodies, and anti-LAG3 antibodies.
 5. The method according to claim4, wherein the at least two immune checkpoint inhibitors are selectedfrom the group consisting of anti-CTLA-4 antibodies and anti-PD-1antibodies.
 6. The method according to claim 5, wherein the at least twoimmune checkpoint inhibitors are selected from the group consisting ofipilimumab, tremelimumab, pembrolizumab, and nivolumab.
 7. The methodaccording to claim 1, wherein the at least two immune checkpointinhibitors comprise an anti-CTLA-4 antibody and an anti-PD-1 antibody.8. The method according to claim 1, wherein the Axl inhibitor and the atleast two immune checkpoint inhibitors are administered concurrently. 9.The method according to claim 1, wherein the Axl inhibitor and the atleast two immune checkpoint inhibitors are administered separatelyand/or sequentially.
 10. The method according to claim 1, wherein thecancer is breast cancer.
 11. A method of controlling cancer in a patientto whom an immune checkpoint inhibitor has been or will be administered,the method comprising administering to a patient in need thereof atherapeutically effective amount of an Axl inhibitor; wherein the Axlinhibitor is a compound of formula (I):

wherein: R¹, R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R⁸,—C(O)N(R⁶)R⁷, and —C(═NR⁶)N(R⁶)R⁷; R² and R³ are each independently apolycyclic heteroaryl containing more than 14 ring atoms optionallysubstituted by one or more substituents selected from the groupconsisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,—R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where pis 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,—R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,—R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); or R² is apolycyclic heteroaryl containing more than 14 ring atoms as describedabove and R³ is selected from the group consisting of aryl andheteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,—R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,—R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,—R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where tis 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and—R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); or R³ is a polycyclicheteroaryl containing more than 14 ring atoms as described above, and R²is selected from the group consisting of aryl and heteroaryl, where thearyl and the heteroaryl are each independently optionally substituted byone or more substituents selected from the group consisting of alkyl,alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹²,—R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)₂, —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2);each R⁶ and R⁷ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,—R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷, together with thecommon nitrogen to which they are both attached, form an optionallysubstituted N-heteroaryl or an optionally substituted N-heterocyclyl;each R⁸ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkynyl; each R⁹ is independently selected from the groupconsisting of a direct bond, an optionally substituted straight orbranched alkylene chain, an optionally substituted straight or branchedalkenylene chain and an optionally substituted straight or branchedalkynylene chain; each R¹⁰ is independently selected from the groupconsisting of an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chainand an optionally substituted straight or branched alkynylene chain;each R¹¹ is independently selected from the group consisting ofhydrogen, alkyl, cyano, nitro and —OR⁸; each R¹² is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl,haloalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,—R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R^(12's), together with thecommon nitrogen to which they are both attached, form an optionallysubstituted N-heterocyclyl or an optionally substituted N-heteroaryl;each R¹³ is independently selected from the group consisting of a directbond, an optionally substituted straight or branched alkylene chain andan optionally substituted straight or branched alkenylene chain; andeach R¹⁴ is independently selected from the group consisting of anoptionally substituted straight or branched alkylene chain and anoptionally substituted straight or branched alkenylene chain; as anisolated stereoisomer or mixture thereof or as a tautomer or mixturethereof, or a pharmaceutically acceptable salt or N-oxide thereof,wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody or ananti-PD-1 antibody; and wherein cancer is an Axl-expressing cancer. 12.The method according to claim 1, further comprising administering to thepatient in need thereof a therapeutically effective amount of one ormore oncolytic viruses in concurrent, separate or sequentialcombination.
 13. The method according to claim 12, wherein the one ormore oncolytic viruses are selected from reovirus, Newcastle diseasevirus, adenovirus, herpes virus, polio virus, mumps virus, measlesvirus, influenza virus, vaccinia virus, rhabdovirus, vesicularstomatitis virus, and derivatives and variants thereof.
 14. The methodaccording to claim 11, wherein an oncolytic virus has also been or willalso be administered.
 15. The method of claim 1, wherein saidcontrolling is delaying spread of cancer.
 16. The method of claim 1,wherein said controlling is minimizing spread of cancer.
 17. The methodof claim 11, wherein said controlling is delaying spread of cancer. 18.The method of claim 11, wherein said controlling is minimizing spread ofcancer.